Cyclization to form cephem ring and intermediates therefor

ABSTRACT

Intermediates represented by the following formulas are useful for synthesizing 3-hydroxy-3-cephem compounds ##STR1## wherein A and B each is a hydrogen or amino substituent; R is a hydrogen or thiol substituent; Hal is a halogen; X is a hydroxy or carboxy protecting group; the broken line between A and R shows that when R and B are hydrogens, and A is a carboxylic acyl, the substituents can be combined to form an azetidinothiazoline bicyclic ring; and the enamine derivatives thereof. One embodiment provides for cyclizing a compound of the formula: ##STR2## wherein A, B, X and Hal are as defined above, which comprises treating the said compound with an acid, base, or solvent if required in the presence of a catalyzer to give a compound represented by following formula ##STR3## In a further embodiment a compound represented by the following formula ##STR4## wherein A, B, R and X are as defined above, is prepared by a process which comprises treating an enamine of a compound represented by following formula ##STR5## wherein A, B, R, X, Hal and broken line are as defined above, with a disubstituted amino containing from 2 to 20 carbon atoms, with the action of an aqueous acid.

This application is a division of application Ser. No. 658,665, filedFeb. 17, 1976, now U.S. Pat. No. 4,079,181.

An intermediate represented by following formula for synthesizing3-hydroxy-3-cephem compounds. ##STR6## wherein A and B each is ahydrogen or amino substituent; R is a hydrogen or thiol substituent; Halis a halogen; X is a hydroxy or carboxy protecting group; the brokenline between A and R shows that when R and B are hydrogens, and A is acarboxylic acyl, the substituents can be combind to form anazetidinothiazoline bicyclic ring; and the enamine derivatives thereof.

This invention relates to the cyclization to form the cephem ring, andthe intermediates therefor. More specifically, it relates to compoundsrepresented by following formula ##STR7## wherein A and B each is ahydrogen or amino substituent; R is a hydrogen or thiol substituent; Halis a halogen; X is a hydroxy or a carboxy protecting group; the brokenline shows that when R and B are hydrogens and A is a carboxylic acyl,the substituents can be combined to form an azetidinothiazoline bicyclicring; and their enamine derivatives, and to the processes for thecyclization to form cephem ring through the said intermediates shownabove by the reactions representable by following reaction scheme:##STR8## wherein A, B, R, Hal, X and the broken line are as definedabove; and Y is a hydroxy or enamine group. When Y is OH, it can be inoxo form.

Many trials for synthesizing 3-cephem ring in large scale have beenreported, but no factory produces cephalosporins by synthesizing thenucleus except for cephalexin. This invention provides mild cyclizationto form 3-hydroxy-3-cephem compounds through 4-mercaptoazetidinonederivatives.

Efforts to cyclize a type of compounds of the formula (2) or (3) where Yis other than hydroxy or a substituted amino resulted in unsatisfactoryresults. However, when Y is a group which promotes enolization to form adouble bond toward the exo-position, the cyclization took place smoothlyto form the objective 3-hydroxy-3-cephem compound (4).

The 3-hydroxy-3-cephem compound (4) are useful intermediates forsynthesizing useful cephem compounds (e.g. recently developed3-methoxy-7-(α-phenylglycinamido)-3-cephem-4-carboxylic acid,3-chloro-7-(α-phenylglycinamido)-3-cephem-4-carboxylic acid,3-bromo-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid).

In the above reaction scheme, the ABN group is an amino or substitutedamino. The said substituted amino can be acylamino, hydrocarbylamino,hydrocarbylideneamino, silylamino, sulfenylamino, or like conventionalprotecting groups containing up to 20 carbon atoms. Such groups areconventional in the field of cephalosporin or penicillin chemistry.

Representative acyls in the said acylamino include inorganic acyls suchas carbonic acyl (e.g. alkoxycarbonyl, aralkoxycarbonyl oraryloxycarbonyl), sulfuric acyl, phosphoric acyl (e.g.dialkoxyphosphinyl, dialkoxythiophosphonyl or alkoxyaminophosphoroyl);and organic acyls such as alkanoyl, cycloalkanoyl, aralkanoyl, aroyl,alkylsulfonyl, arylsulfonyl or alkylphosphonyl. These groups can, wherepossible, be interrupted by a hetero atom in their skeleton or can beunsaturated or substituted by, for example, halogen (e.g. fluorine,chlorine, or bromine, nitrogen function (e.g. amino, hydrazino. azido,alkylamino, arylamino, acylamino, alkylideneamino, acylimino, imino ornitro), oxygen function (e.g. hydroxy, alkoxy, aralkoxy, aryloxy,acyloxy or ozo), sulfur function (e.g. mercapto, alkylthio, aralkylthio,arylthio, acylthio, thioxo, sulfo, slfonyl, sulfinyl, alkoxy-sulfonyl,or aryloxysulfinyl), carbon function (e.g. alkyl, alkenyl, aralkyl,aryl, carboxy, carbalkoxy, carbamoyl, alkanoyl, aroyl, aminoalkyl,aralkanoyl or cyano), or phosphorous function (e.g. phospho orphosphoroyl). A and B can also be considered together as forming adiacyl group of a polybasic acid (e.g. phthaloyl,pyridine-2,3-dicarbonyl, maleoyl or succinoyl).

More preferable groups in the said acyl can be the acyls of penicillinside chain (e.g. phenylacetyl, phenoxyacetyl, heptanoyl), or theseconvertible to a group profitable for the antibacterial activity of theend products (e.g. hydrogen, N-tertiary butoxy-2-phenylglycinamido,α-(1-carbomethoxy-1-isopropen-2-yl)amino-α-phenylglycyl,4-phenyl-2,2-dimethyl-5-oxo-1,3-imidazolidin-1-yl,α-diphenylmethoxycarbonyl-α-phenylacetamido).

The hydrocarbon groups which may be represented by A and/or B can beeasily removable aliphatic hydrocarbon groups contaning from 1 to 20carbon atoms (e.g. alkyl, alkenyl, aralkyl or other aliphatichydrocarbon groups) or easily removable mono-cyclic aromatic hydrocarbongroups (e.g. phenyl or pyrimidyl). These groups can, where possible, beinterrupted by a hetero atom in the skeleton thereof or can beunsaturated or substituted by a substituent (e.g. halogen atom ornitrogen, oxygen, sulfur, carbon or phosphorous functions). A and B canalso be considered together as forming a divalent hydrocarbon group(e.g. alkylene, aralkylene, alkylidene, aralkylidene, α-halo- oralkoxy-aralkylidene, diarylmethylidene or cycloalkylidene), which can,where possible, be interrupted by a hetero atom in the skeleton thereofor can be substituted by a substituent as cited above or can beunsaturated.

When group A is acyl and group B is a hydrocarbon, they can be combinedtogether with the nitrogen atom bound to position 7 of the cephem ringto form a cyclic group (e.g. a 4-oxo-3-imidazolidinyl ring).

The silyl (e.g. trialkylsilyl) and sulfenyl (e.g. phenylsulfenyl oro-nitrophenylsulfenyl) groups which may be represented by A and/or B areconventional amino protecting groups.

Representative acyl groups for A and B in the above formula (I) includefollowing groups:

(1) alkanoyl containing from 1 to 5 carbon atoms;

(2) haloalkanoyl containing from 2 to 5 carbon atoms;

(3) azidoacetyl;

(4) cyanoacetyl;

(5) acyl groups of the formula:

    Ar--CQQ'--CO--

in which Q and Q' are each hydrogen or methyl; and Ar is phenyl,dihydrophenyl or a monocyclic heterocyclic aromatic group containingfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and/or sulfuratoms, and may optionally be substituted by an inert group e.g. an alkylor alkoxy group containing from 1 to 3 carbon atoms, chlorine, bromine,iodine, fluorine, trifluoromethyl, hydroxy, cyano, aminomethyl, amino ornitro;

(6) acyl groups of the formula:

    Ar--G--CQQ'--CO--

in which G is an oxygen or sulfur; and Ar, Q, and Q' are as definedabove;

(7) acyl groups of the formula:

    Ar--CHT--CO--

in which Ar is as defined above; and T is (i) amino, ammonium, aminosubstituted by such conventional amino-protecting groups asbenzyloxycarbonyl, alkoxycarbonyl containing from 1 to 4 carbon atoms,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl,cyclopropylmethoxycarbonyl, methanesulfonylethoxycarbonyl,triphenylmethyl, 2,2,2-trichloroethoxycarbonyl, guanidylcarbamoyl,optionally substituted ureido carbonyl including3-methanesulfonylimidazolidon-1-ylcarbonyl, alkanoyl containing from 1to 5 carbon atoms, pyronecarbonyl, thiopyronecarbonyl, pyridonecarbonyl,homo- or hetero-cyclic mono-cyclic aromatic acyl optionally substitutedby hydroxy, lower alkanoyloxy containing from 1 to 3 carbon atoms,halogen, trifluoromethyl or alkyl containing from 1 to 3 carbon atoms,aminoalkyl containing from 1 to 3 carbon atoms, or hydroxy alkylcontaining from 1 to 3 carbon atoms, or amino protected in the forms ofphthalimido or enamines derived from acetoacetates, acetylacetone,acetoacetamide, or acetoacetonitrile, (ii) hydroxy or acyloxy containingfrom 1 to 7 carbon atoms, carbamoyloxy, or aralkyloxy containing from 7to 12 carbon atoms, (iii) carboxy or alkoxycarbonyl containing from 2 to7 carbon atoms, indanyloxycarbonyl, phenoxycarbonyl, or (iv) azido,cyano, carbamoyl, alkoxysulfonyl, sulfo, or alkoxysulfonyl;

(8) 2-sydnon-3-alkanoyl containing from 3 to 5 carbon atoms;

(9) (2- or 4-pyridon-1-yl)acetyl;

(10) 5-aminoadipoyl, 5-aminoadipoyl protected at the amino group byaroyl or alkanoyl containing from 1 to 10 carbon atoms, chloroalkanoylcontaining from 1 to 5 carbon atoms or alkoxycarbonyl containing from 2to 10 carbon atoms; or 5-aminoadipoyl protected at the carboxy group bybenzhydryl, 2,2,2-trichloroethyl, trialkylsilyl, alkyl containing from 1to 6 carbon atoms, nitrobenzyl or methoxybenzyl; and

(11) acyl groups of the formula:

    L--O--CO--

in which L is an easily removable optionally substituted hydrocarbongroup containing from 1 to 8 carbon atoms (e.g. 2,2,2-trichloroethyl,isobornyl, tertiary butyl, 1-methylcyclohexyl, 2-alkoxy tertiary butyl,benzyl, p-nitrobenzyl or p-methoxybenzyl).

Alternatively, A and B considered together can represent a diacyl groupderived from a polybasic carboxylic acid containing from 4 to 12 carbonatoms, alkylidene containing from 1 to 6 carbon atoms or arylmethylidenecontaining from 7 to 9 carbon atoms.

In the above, examples of Ar groups are furyl, thienyl, pyrryl,oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl,isothiazolyl, thiadiazolyl, thiatriazolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazinyl and dihydrophenyl, each being optionallysubstituted by halogen, alkyl containing from 1 to 3 carbon atoms,hydroxy, aminomethyl or alkoxy containing from 1 to 3 carbon atoms.

The carboxy protecting group which is represented by X can contain up to20 carbon atoms and can be an oxygen function such as, for example,alkoxy containing from 1 to 8 carbon atoms (e.g. methoxy, ethoxy ortertiary butoxy), aralkoxy containing from 7 to 20 carbon atoms (e.g.benzyloxy, methoxybenzyloxy, nitrobenzyloxy, diphenylmethoxy ortrityloxy), mono- or bi-cyclic aryloxy (e.g. phenoxy or naphthyloxy), ororgano metaloxy (e.g. trimethylstannic oxy or trimethylsilyloxy),organic or inorganic acyloxy containing up to 8 carbon atoms, or metaloxy of groups I, II or III in the periodical table (e.g. sodiooxy,potassiooxy, or magnesiodioxy); or X may be selected from sulfurfunctions such as those forming thiol ester, thiocarboxy or like groups;nitrogen functions such as these forming amides, hydrazides, azide orlike groups; or X may be selected from other carboxy-protecting groups.

These groups can, where possible, be interrupted by a hetero atom in thenucleus, unsaturated, or substituted by a substituent such as thosereferred to above (e.g. the nitrogen, oxygen, sulfur, carbon orphosphorous functions referred to above or halogen). Among preferablecarboxy protecting groups X are those forming haloalkyl esterscontaining from 1 to 5 carbon atoms, acylalkyl esters containing from 2to 10 carbon atoms, alkoxyalkyl- or aminoalkyl esters containing from 2to 8 carbon atoms, arylester or aralkyl esters containing from 7 to 20carbon atoms, esters with an oxime containing from 2 to 10 carbon atoms,N-alkoxyamide containing from 1 to 5 carbon atoms, imide with saccharin,imide with phthalimide, N,N'-diisobutylhydrazide, metal salts, oralkylamine salts containing from 1 to 6 carbon atoms, or groupsequivalent in effect to these groups (in the above, specified numbers ofcarbon atoms are for groups X).

Antibacterially preferred carboxy-protecting groups X include thesewhich form acyloxymethyl esters, phenacyl esters, the benzaldoximeester, the N,N-dimethylaminomethyl ester, alkali metal salts, alkalineearth metal salts, acylated alkaline earth metal salts, and other groupsequivalent in effect to these groups. Preferred carboxy protectinggroups X include tert butoxy benzyloxy, benzhydryloxy, p-nitrobenzyloxy,p-methoxybenzyloxy, 2,2,2-trichloroethoxy and alkali metal-oxy.

Halogen which may be represented by Hal in the formulae can be achlorine, bromine, iodine, or fluorine, in which chlorine and bromineare most preferable.

The thiol substituent R can be that easily removable without adverseeffect on the other part of the molecule prior to or during cyclizationreaction. It can be an acyl group, e.g. tertiary butoxycarbonyl,carbobenzoxy, cyclopropylmethoxycarbonyl, cyclopropylethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-methanesulfonylethoxycarbonyl);1-alkoxy or acyloxyalkyl group containing 2 to 10 carbon atoms (e.g.methoxymethyl, ethoxymethyl, acetoxymethyl, 1-benzoyloxyethyl), mono- ordicyclic aromatic thio group (e.g. thiadiazolylthio, thiazolylthio,benzothiazolylthio, phenylthio, o-nitrophenylthio, naphthylthio); andlike groups.

As stated above, A, B, and R can be combined to form anazetidinothiazoline ring system represented by following formula:##STR9## wherein R' is a group of an acyl represented by R'CO--; Hal, Xand Y are as defined above, which can easily be hydrolyzed with anaqueous acid to give 4-mercapto-3-R'CONH-azetidinone compounds.

The enamine derivatives of the compound (I) are the compounds (I) wherethe hydroxy group is substituted by an amino group containing from 2 to20 carbon atoms. Preferable amino groups include dialkylamino,alkylaralkylamino, alkylalkenylamino, alkylencamino, diaralkylamino,dialkenylamino and like amino groups optionally substituted by an inertgroup, the main nucleus of which can be interrupted by a hetero atom.The groups are of intermediate character, and it is removed from theproduct in the final step. Therefore, the type of the group can bevaried considerably, so far as the object of the reactions is notdisturbed by the variation. Most preferable groups are morpholino,alkylenamino containing 4 to 8 carbon atoms, dialkylamino containing 2to 6 carbon atoms, diaralkylamino containing 14 to 20 carbon atoms,optionally substituted by an inert group e.g. alkyl or halogen. Theenamino group has advantage over other various substituents in that itfacilitates desired halogenation, and that it is hydrolyzed under mostmild condition, as is explained later.

More preferable compounds (I) provided by this invention are representedby following formulae ##STR10## wherein A is a phenylacetyl orphenoxyacetyl; B is a hydrogen; R is a hydrogen, methoxymethyl,carbobenzoxy, cyclopropylmethoxycarbonyl, or benzothiazol-2-ylthio; Halis a chlorine or bromine; X is a methyl, benzyl, p-nitrobenzyl,benzhydryl, or 2,2,2-trichloroethyl; Y is a piperidino, morpholino,dimethylamino, or hydroxy; and R' is a benzyl or phenoxymethyl, and whenY is a hydroxy, it can be in an oxo form.

Another class of compounds provided by this invention is represented bythe following formula ##STR11## wherein ABN is an amino or substitutedamino containing up to 20 carbon atoms; R² is a hydrogen or thiolsubstituent containing up to 20 carbon atoms; X is a hydrogen or thiolsubstituent containing up to 20 carbon atoms; X is a hydroxy or carboxyprotecting group containing up to 20 carbon atoms; Acyl is a carbonicacyl group containing up to 20 carbon atoms; and Y" is a disubstitutedamino containing 2 to 20 carbon atoms.

More preferable compounds are represented by the above formula in whichABN is a phenoxyacetamide, R² is a carbobenzoxy,cyclopropylmethoxycarbonyl, methoxymethyl, or benzothiazol-2-ylthio, Xis a 2,2,2-trichloroethoxy or p-nitrobenzyloxy, Acyl is acyclopropylmethoxycarbonyl, carbobenzoxy, methanesulfonyl, ortoluene-p-sulfonyl, Y" is a morpholin-4-yl, or piperidin-1-yl, and Halis a bromine; or in which ABN is a phthalimido, R² and Acyl each is acarbobenzoxy or cyclopropylmethoxycarbonyl, X is a methoxy, Y" is apiperidin-1-yl or morpholin-4-yl, and Hal is a bromine.

A mercaptoazetidine compound represented by following formula is alsoprepared easily by the deprotection method of this invention: ##STR12##wherein ABN and X are as defined above; and R³ is a hydrogen,isopropenyl, isopropylidene, or 1-hydroxyethylidene.

More preferable mercaptoazetidine compounds are represented by the aboveformula in which ABN is a phenoxyacetamido, X is a p-nitrobenzyloxy, andR³ is a isopropenyl, isopropylidene, or 1-hydroxyethylidene, or in whichABN is a phenoxyacetamido, X is a 2,2,2-trichloroethoxy, and R³ is a1-hydroxyethylidene; or in which ABN is a phenoxyacetamido, X is atertiary butoxy, and R³ is a hydrogen; or in which ABN is aphenylacetamido, X is a p-nitrobenzyloxy, and R³ is a isopropenyl.

A sulfoxylated azetidine compound represented by following formula alsois a useful starting material for the process provided by thisinvention: ##STR13## wherein R' is a group of an acyl group R'CO--; X isas defined above; and Z is an aliphatic or aromatic sulfonyl containingup to 20 carbon atoms.

More preferable compounds are represented by the above formula in whichR' is a phenoxymethyl, Z is a methanesulfonyl, and X is ap-nitrobenzyloxy, 2,2,2-trichloroethoxy, benzyloxy, or henzhydryloxy; orin which R' is a benzyl, Z is a methanesulfonyl, and X is ap-nitrobenzyloxy, 2,2,2-trichloroethoxy, benzyloxy, or benzhydryloxy; orin which R' is a phenoxymethyl; Z is a toluene-p-sulfonyl, and X is ap-nitrobenzyloxy, or 2,2,2 -trichloroethoxy.

The sulfoxylated compounds can be treated by a secondary aminecontaining 2 to 20 carbon atoms to give enamine compounds provided bythis invention and represented by following formula ##STR14## wherein R'and X are as defined above; and Y" is a disubstituted amine containing 2to 20 carbon atoms.

More preferable enamine compounds are represented by the above formulain which R' is a phenoxymethyl, X is a p-nitrobenzyloxy,2,2,2-trichloroethoxy, benzyloxy, or benzhydryloxy, and Y" is amorpholino; or in which R' is a benzyl, Y" is a morpholino, and X is ap-nitrobenzyloxy, 2,2,2-trichloroethoxy, benzyloxy, or benzhydryloxy; orin which R' is a benzyl, Y" is a dimethylamino, and X is ap-nitrobenzyloxy; or in which R' is a benzyl, Y" is a piperidino, and Xis a 2,2,2-trichloroethoxy.

The enamine compounds can be halogenated mildly to give haloenaminecompounds provided by this invention, represented by following formula##STR15## wherein R', X, and Y" are as defined above, and Hal is ahalogen.

More preferable haloenamine comounds are represented by the aboveformula in which R' is a phenoxymethyl, Y" is a morpholino, Hal is abromine, and X is a p-nitrobenzyloxy, 2,2,2-trichloroethoxy, benzyloxy,or benzhydryloxy; or in which R' is a benzyl, Y" is a morpholino, Hal isa bromine, and X is a p-nitrobenzyl, 2,2,2-trichloroethoxy, benzyloxy,or benzhydryloxy; or in which R' is a phenoxymethyl, Y" is a morpholino,Hal is a chlorine, and X is a p-nitrobenzyloxy; or in which R' is abenzyl, Y" is a dimethylamino, Hal is a bromine, and X is ap-nitrobenzyloxy; or in which R' is a benzyl, Y" is a piperidino, Hal isa bromine, and X is a 2,2,2-trichloroethoxy.

The haloenamine compounds are hydrolyzed mildly to give enol compoundsrepresented by following formula, which also are compounds provided bythis invention: ##STR16## wherein R', X, and Hal are as defined above,or that in its oxo form.

More preferable enol compounds are represented by above formula in whichR' is a phenoxymethyl, Hal is a bromine, and X is a p-nitrobenzyloxy,2,2,2-trichloroethoxy, benzyloxy, or benzhydryloxy, or in which R' is aphenoxymethyl, Hal is a bromine, and X is a p-nitrobenzyloxy,2,2,2-trichloroethoxy, benzhydryloxy, or benzyloxy; or in which R' is abenzyl, Hal is a bromine, and X is a p-nitrobenzyloxy,2,2,2-trichloroethoxy, benzyloxy, or benzhydryloxy; or in which R' is aphenoxymethyl, X is a p-nitrobenzyloxy, and Hal is a chlorine.

The haloenamine compound can also be hydrolyzed to give amercaptoenamine compounds represented by following formula, which arealso compounds provided by this invention. ##STR17## wherein ABN, X, Haland Y" are as defined above.

More preferable mercaptoenamine compounds are represented by aboveformula in which ABN is a phenoxyacetamido, X is a p-nitrobenzyloxy,2,2,2-trichloroethoxy, benzyloxy, or benzhydryloxy, Y" is a morpholinoor dimethylamino, and Hal is a bromine; or in which ABN is aphenylacetamido, X is a p-nitrobenzyloxy, 2,2,2-trichloroethoxy,benzyloxy, or benzhydryloxy, Y" is a morpholino or piperidino, and Halis a bromine; or in which ABN is a phenoxyacetamido, X is ap-nitrobenzyloxy, Y" is a morpholino, and Hal is a chlorine.

The enol or mercaptoenamine compounds can be hydrolyzed to give the lastintermediates of the process, namely mercaptoenol compounds representedby following formula, which also are compounds provided by thisinvention. ##STR18## wherein ABN, X, and HAL are as defined above, orthat in its oxo form.

More preferable mercaptoenol compounds are represented by above formulain which ABN is a phthalimido, X is a methoxy, and Hal is a bromine; orin which ABN is a phenoxyacetamido, Hal is a bromine, and X is ap-nitrobenzyloxy, 2,2,2-trichloroethoxy, benzyloxy, or diphenylmethoxy;or in which ABN is a phenylacetamido, Hal is a bromine, and X is ap-nitrobenzyloxy, 2,2,2-trichloroethoxy, benzyloxy, or benzhydryloxy, orin which ABN is a phenoxyacetamido, X is a p-nitrobenzyloxy, and Hal isa chlorine.

The starting materials (1) for the cyclization reactions, 4-substitutedthio-3-(amino or substitutedamino)-2-oxo-α-(1-ethylidene)azetidine-1-acetic acid or the derivativesat their carboxy group can be prepared from penicillin 1-oxide byreaction of phosphite esters, acetic anhydride, etc., givingα-isopropenyl-azetidine-1-acetic acid or its derivatives; which isoxidized with ozone to give the starting material where theα-substituent is 1-hydroxyethylidene or 1-acetyl; which in turn istreated with acylating reagents, aminating reagents, reactive nitrogenintroducing reagents, etc., to give the corresponding startingmaterials. Further, the starting materials can also be prepared from anazetidine-2-one derivative and a reactive derivatives of acetoaceticacids.

the process (1) can be effected by treating the compound (1) with ahalogenating regent. The halogenating reagent includes that whichhalogenates through halogen cation or halogen radical or itsequivalents. Representative halogenating reagents belong to thecategories illustrated below:

1. X'₂

X'₂, brCl, IBr, C₆ H₅ I.X'₂, C₅ H₅ N.HX'.X₂, C₆ H₅ N(CH₃)₂ X'.X'₂,(alkyl)₂ SO₄. HX' .CuX'₂.

2. --ox'

(alkyl)OX',HOX', (acyl)OX'.

3. ═nx' (acyl)NHX'

(alkyl)₄ NH'.X'₂, NO₂ X', (acyul)NHX', (Acyl)₂ NX'.

4. --sx'

sx'₂, s+x₂.

5. --cx'

x'₂ choch₃, cx'₄, α-haloketones, α-halosulfone, or like reagents

where alkyl and acyl contain up to 7 carbon atoms; and X' is a chlorine,bromine or iodine.

When these halogenating reagents are used as those through halogenradicals, the reaction is carried out by mediation with heat, lightperoxide (peracid, peroxide, hydroperoxide, etc.), azo compound(azobisisobutyronitrile, etc.), or other radial initiator.

When these halogenating reagents are used as those through halogencation, the reaction is carried out, if required, in the presence of anacid trapping reagent (organic or inorganic base e.g. sodium carbonate,pyridine, quinoline, lutidine, diethylamine, triethylamine, etc.). Theonium ion forming starting compounds (1) are more easily halogenated togive the objective compounds in higher yield under mild condition.

When these halogenating reagents are used through carbanion of thestarting material (1), the starting materials (1) are treated with ananion forming reagent (alkali metal hydrides, alkali metal amides,alkali metal alkoxide, lithium dialkylamine, hexaalkyldisilazanelithium, trialkylamine, Grignard reagents etc.) to form carbonion,followed by the action of a halogenating reagent. The reaction ispreferably carried out in an aprotic solvent at lower temperature, so asto avoid side reactions.

The reaction of the starting materials with the halogenating reagents ispreferably carried out in an inert solvent.

The solvents include a hydrocarbon (pentane, hexane, benzene, toluene,etc.), halogenated hydrocarbon (methylene chloride, chloroform, carbontetrachloride, dichlorobenzene, etc.), ester (ethyl acetate, butylacetate, methyl benzoate, etc.), ketone (acetone, cyclohexanone,benzophenone, etc.), ether (diethyl ether, ethyleneglycol dimethylether, tetrahydrofuran, tetrahydropyran, dioxane, morpholine, anisole,etc.), alcohol (methanol, ethanol, ethyleneglycol, benzylalcohol, etc.),carboxylic acid (acetic acid, propionic acid, etc.), base (butylamine,triethylamine, pyridine, picoline, etc.), amide (dimethylformamide,dimethylacetamide, hexamethylphosphorotriamide, etc.), nitrile(acetonitrile, benzonitrile, etc.), nitrohydrocarbon, sulfoxide(dimethyl sulfoxide, etc.), water, liquid ammonia solvents, and othersolvents and their mixtures.

Especially preferable solvents are aromatic hydrocarbon, halogenatedhydrocarbon, ester, ether, amide, and acid, solvents.

The cis-trans isomerization possibly occurs during the reaction at thesubstituent on position α of the geometric isomer, which reaction isincluded in the scope of this invention.

Halogenation of compounds representable by the formula (1) provided Y isother than amino took place smoothly in some cases and with difficultyin other cases. Main difficulty were the position where the halogenatoms was introduced. In other words, the priority of the desiredposition to other position in the molecule for halogenation was rathersmall, and it differs from one compound to another. Another factor whichrestricts Y to the scope given above is found not in the halogenationbut in the following reactions, i.e. (i) ease of deprotection to give acompound (I) where Y is hydroxy; and (ii) ability to cyclize giving thedesired cephem compound (4). The compounds representable by formula (1)provided Y is other than hydroxy cyclized unefficiently orinsignificantly. From these observations, Y is restricted to include ahydroxy and substituted amino, as is explained above.

The deprotection (2) of the compound (2) can be carried out by treatingthe compound (2) with aqueous acid for the thiazolinoazetidine compound,and by treating the compound (2) where R is a carbonic acyl, with aLewis acid.

The decomposition of the azetidinothiazoline compound with an aqueousacid is a new generic reaction for obtaining the 4-mercapto-3-carboxylicacylamino-2-oxoazetidine derivatives according to the reaction scheme##STR19## wherein R' is a group of an acyl group R'CO; R" is a hydrogenor hydrocarbon group (e.g. alkyl, alkenyl, aralkyl, aryl), acyl derivedfrom organic or inorganic acid, silyl, sulfenyl, or other monovalentamino protecting group, optionally substituted by a halogen, sulfur,oxygen, nitrogen, carbon, or phosphorous functions referred to above.

It can be carried out by treating a thiazolinoazetidine (5) with an acidand water. The reaction of water is necessary for cleavage of thiazolinering to give 4-mercapto and 3-acylamine of azetidine ring. Thepreferable acids include mineral acid (e.g. hydrogen halide, sulfuricacid, nitric acid, phosphoric, acid, perchloric acid, chloric acid),sulfonic acid (e.g. alkanesulfonic acid, arylsulfonic acid,aralkylsulfonic acid, especially α-haloalkanesulfonic acid),α-halocarboxylic acid, polycarboxylic acid, preferably acids havingdissociation constants of at least 001. More specific acids includestrong acids e.g. perchloric acid, trifluoroacetic acid, trichloroaceticacid, dichloroacetic acid, trifluoromethanesulfonic acid,trichloromethanesulfonic acid, hydrogen borofluoride, hydrochloric acid,hydrogen fluoride, hydrobromic acid, nitric acid, phosphoric acid,benzenesulfonic acid, toluenesulfonic acid, bromobenzenesulfonic acid,methanesulfonic acid, ethanesulfonic acid, etc.

The said reaction can be carried out in a solvent referred to above.

More preferable solvents are polar solvents capable of dissolving waterand acid (e.g. ether, ketone, alcohol, amide, sulfoxide, water), thesolvents capable of dissolving the starting material (5) (e.g.halohydrocarbon, ester, ether, ketone), and the mixture thereof.

When a strong acid is used, side reaction e.g. decomposition of theazetidinone ring, can take place. The yield can be improved by selectionof reaction conditions e.g. concentration, temperature, reaction time,etc. Generally, the reaction proceeds even at room temperature rapidly,sometimes within 10 minutes to 1 hour, to give the objective compound inhigh yield.

The products are unstable to alkali and oxidation. Therefore, reactionsand working up should be done without exposure to such conditions.

Further, the preparation of the mercapto compound (8) by eliminating thethiol substituent R being carbonic acyl can be carried out by treatingthe compound (7) with a Lewis acid according to the reaction scheme##STR20## wherein A, B, X, Y', and Hal are as defined above; and R'" isa hydrocarbyl containing 1 to 20 carbon atoms optionally substituted byan inert group e.g. halogen aralkyl, nitro, alkoxy or alkyl containing 1to 5 carbon atoms, or carbalkoxy. The carbonic acyl can be carbobenzoxy,tertiary butoxycarbonyl, cyclopropylmethoxycarbonyl,2,2,2-trichlorothoxycarbonyl, methanesulfonylethoxycarbonyl,isobornyloxycarbonyl), and the Lewis acid can be boron trihalide,aluminum halide, titanium dihalide, titanium tetraalkanoate, and likeLewis acids. The reaction can be carried out mildly in high yield.

The cyclization (3) can be effected by treating the compound (3) with an

(i) acid,

(ii) base, or

(iii) solvent, if required in the presence of catalyzer, or under anycondition which cyclizer the starting material to give 3-cephem nucleus.The starting compounds seemed to have tendency to cyclize nearlyautomatically, and under various weak conditions, the object cephemcompounds can be isolated in good yield. The mercapto group at position4 of the starting materials can be in the form of mercaptide anion. Itis unnecessary to use the isolated starting material (3) for thereaction, and every method which yields the starting material (I) whereR is a hydrogen can be used for the reaction. Typical examples of themethod are treatment of α-[3-(phenoxymethyl orbenzyl)-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-haloacetyl)aceticacid, α-[4-mercapto-3-(phenoxyacetyl orphenylacetyl)amino-2-oxoazetidin-1-yl]-α-(2-haloacetyl)acetic acid, ortheir derivatives at the carboxy or their enamine derivatives at theα-(2-haloacetyl) group, under aqueous acid condition. The treatment isconsistent with the condition for cyclization cited above (i), and theobtained product is the objective cephem compound (4)

The acids used to acidify the reaction medium include a mineral acid(e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, perchloric acid, sulfurous acid), sulfonic acid (e.g.alkanesulfonic acid, arysulfonic acid), phosphonic acid, carboxylic acid(e.g. formic acid, acetic acid, haloalkanoic acid, oxalic acid, phthalicacid), and other organic or inorganic acid, or their salts with a weakbase (e.g. aromatic or aliphatic base, ammonia, alkaline earth metal,aluminum, silver), or acidic salts of the said acid with common baseincluding an alkali metal salts. Lewis acids can also be used favourablyin an aprotic solvent.

The bases used to make the medium basic include preferably the said weakbase. Strong bases (e.g. alkali metal hydroxide, alkali metal carbonate,tertiary ammonium hydroxide), can be used under selected mild conditionbecause they decompose the starting or produced compounds, especiallythe β-lactam moiety. Lewis base can also be used.

The catalyst for cyclization can be a neutral or basic silica gel,alumina, diatomaceous earth, florisil, and other catalysts.

In some cases, cyclization takes place by the action of solvent (e.g.solvent of higher polarity including amides(hexamethylphosphorotriamide, dimethylformamide, formamide, etc.)alcohol, water.) alone. In the cases, polar solvents accelerate thereaction. It can be assumed the reaction is a result of catalysis withhydrogen halide produced by the initial reaction.

The reaction is preferably carried out in a solvent referred to aboveunder heating or cooling, or at room temperature. If required, thereaction medium is stirred under inert gas.

Preferable solvents are polar solvent e.g. alcohol, carboxylic acid,amide, nitrile, nitrohydrocarbon, sulfoxide, water solvents, and asolvents highly capable of solubilizing the starting materials, e.g.ester, ether, halohydrocarbon solvents which sometimes facilitates thereaction. The reaction generally proceeds quickly at room temperature togive the objective cephem or cepham compounds in high yield.

The reaction product (2)-(4) can be isolated from the reaction mixtureby conventional methods e.g. removing unreacted material, by-products,solvent, or the like, and be purified by conventional method e.g.recrystallization, chromatography, reprecipitation.

The final products are 3-hydroxy-3-cephem-4-carboxylic acid or3-oxocepham-4-carboxylic acid (4). In some instances, the substituentsat position 3 or 7 on the cephem ring change during the reaction orworking up, and as a result, the corresponding substituents in thestarting and produced materials differ each other. If desired, suchsubstituents can be recovered or transformed into other required one byconventional methods. Such cases are also included in the scope of thepresent invention.

In the cephem nucleus of the products, there is a double bond linked tocarbon atoms at position 3. The double bond can be directed to position2,4, or the 3-substituent oxygen, or their mixture, according to thecondition of reaction, working up, etc. These cases are also included inthe scope of this invention, but usually, the main product hasexclusively in 3-cephem or 3-oxo double bond isomer.

During the cyclization, it is certain to form intermediary compounds (3)regardless of whether isolation has been carried out or not.

The halogenation (1), deprotection (2), and cyclization (3) can becarried out in one pot, namely without isolating intermediates, and evenwithout removing each reaction solvents. Therefore, the reactionspractically be done as simply as one step reaction (see Examples 2(2)and (3), and Examples 9 to 17 of Part III Cyclization).

Some of the starting materials are prepared by the following procedures.

PREPARATION 1.

To a solution of methylα-[4-mercapto-3-phthalimido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate(100 mg) in tetrahydrofuran (3 ml) is added benzyl chloroformate (100mg), and the mixture is cooled to -65° C. To the solution is addedtriethylamine (60 mg) and stirred for 1 hour. After warming to roomtemperature, the mixture is evaporated. Purification of the residue bychromatography over silica gel gives methylα-[4-benzyloxycarbonylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-(1-benzyloxycarbonylethylidene)acetate(160 mg). Yield: 94%. The product contains no isomer at position α. IR:ν_(max) ^(CHCl).sbsp.3 1790, 1780, 1730 cm⁻¹. NMR: δ^(CDCl).sbsp.38.00-7.50m4H, 7.40s5H, 7.30s5H, 6.27d(5Hz)1H, 5.90d(5Hz)1H, 5.27s2H,5.17s2H, 3.70s3H, 2.47s3H.

PREPARATION 2

To a solution of methylα-(4-mercapto-3-phthalimido-2-oxoazetidin-1-yl)-α-(1-hydroxyethylidene)acetate(50 mg) in tetrahydrofuran (2 ml) is added cyclopropylmethylchloroformate (50 mg), and the mixture is cooled to -65° C., followed bythe addition of triethylamine (30 mg) in tetrahydrofuran (0.5 ml). Afterstirring for 1 hour, the mixture is warmed slowly to room temperature,evaporated under reduced pressure, and purified by chromatography oversilica gel using benzene containing 5% ether to give methylα-[4-cyclopropylmethoxycarbonylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-(1-cyclopropylmethoxycarbonyloxyethylidene)acetate(61 mg). Yield: 79%.

The product is a mixture of the geometric isomers of the substituent atposition α (ca. 3:2). IR: ν_(max) ^(CHCl).sbsp.3 1790, 1780, 1730 cm⁻¹.NMR: δ^(CDCl).sbsp.3 8.00-7.60m4H, 60j8d(5Hz)3/5H, 6.10d(5Hz)2/5H,5.85d(5Hz)3/5H, 5.78d(5Hz)2/5H, 4.30-3.80m4H, 3.87s6/5H, 3.82s9/5H,2.53s6/5H, 2.47s9/5H, 1.60- 0.90m2H, 0.90-0.10m8H.

PREPARATION 3

To a solution of 2,2,2-trichloroethylα-[4-(2-benzothiazolyl)dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetatein tetrahydrofuran are added an acid chloride and triethylamine, and themixture is let react for 1 to 3 hours, and is worked up by conventionalmethod to give following esters:

(1) 2,2,2-trichloroethylα-[4-(2-benzothiazolyl)dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-methanesulfonyloxyethylidene)acetate,IR: ν_(max) ^(CHCl).sbsp.3 3440, 1795, 1753, 1698, 1640, 1602 cm⁻¹. NMR:δ^(CDCl).sbsp.3 2.70s3H, 3.38s3H, 4.6m4H, 5.25d (5Hz)1H, 5.78d(5Hz)1H,6.8-8.0m10H;

(2) 2,2,2-trichloroethylα-[4-(2-benzothiaxolyl)dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-toluene-p-sulfonyloxyethylidene)acetate,IR: ν_(max) ^(CHCl).sbsp.3 3420, 1780, 1770, 1685 cm⁻¹. NMR:ν^(CDCl).sbsp.3 2.28s3H, 2.50s3H, 4.55s2H, 4.63ABq(12Hz)2H,5.08dd(7;5Hz)1H, 5.78d(5Hz)1H, 6.65- 8.22m14H;

(3) p-nitrobenzylα-[4-(2-benzothiazolyl)dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-cyclopropylmethoxycarboxylethylidene)acetate,IR: ν_(max) ^(CHCl).sbsp.3 3420, 1780, 1685, 1640 cm⁻¹. NMR:δ^(CDCl).sbsp.3 0.05-1.52m5H, 2.47s3H, 3.95+4.02d(2H), 4.50+4.58s2H,4.80-5.40m4H, 6.67-8.13m14H.

(4) 2,2,2-trichloroethylα-[4-(2-benzothiazolyl)dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-cyclopropylmethoxycarboxyethylidene)acetate,IR: ν_(max) ^(CHCl).sbsp.3 3450, 1790, 1690, 1650 cm⁻¹. NMR:δ^(CDCl).sbsp.3 0.13-1.55m5H, 2.52s3H, 4.10d(7Hz)2H, 4.53ABq(12Hz)2H,4.62s2H, 5.15 dd(7;5Hz)1H, 5.75d(5Hz)1H, 6.72-07m10H.

PREPARATION 4

To a solution of p-nitrobenzylα-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate(904 mg) in a mixture (9.5 ml) of tetrahydrofuran andhexamethylphosphorotriamide (20:1) are added methanesulfonyl chloride(0.26 ml) and triethylamine (0.37 ml). After 2 hours, the reactionmixture is poured into ice water, and extracted with chloroform. Theextract solution is washed with water, dried, and evaporated to givep-nitrobenzylα-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-methanesulfonyloxyethylidene)acetate(1.12 g). Yellow foam. IR: ν_(max) ^(CHCl).sbsp.3 3426, 1785,1722-1704br, 1640, 1601, 1160, 1175, 986 cm⁻¹. NMR: δ^(CDCl).sbsp.30.32-1.25m5H, 2.57s3H, 2.72s3H, 3.99d(7Hz)2H, 4.55s2H, 5.33-5.99m4H,6.82- 7.62m7H, 8.21d(8.5Hz)2H.

According to similar acylation, following compounds are prepared.

(1) p-nitrobenzylα-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-methoxycarbonyloxyethylidene)acetate,IR: ν_(max) ^(CHCl).sbsp.3 1780, 1731, 1643, 1612, 1601 cm⁻¹. NMR:δ^(CDCl).sbsp.3 0.2-1.33m5H, 2.34s3/2H, 2.50s3/2H, 3.74s3/2H, 3.83s3/2H,3.97d (7Hz)2H, 4.52s2H, 5.26s2H, 5.53-6.00m2H, 6.79-8.24m9H.

(3) 2,2,2-trichloroethylα-[4-(o-nitrophenyl)dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-.alpha.-(1-cyclopropylmethoxycarbonyloxyethylidene)acetate,IR: ν_(max) ^(CHCl).sbsp.3 3430, 1781, 1750sh, 1685, 1640 cm⁻¹. NMR:δ^(CDCl).sbsp. 0.2-1.4m5H, 2.50s3H, 4.13d(8Hz)2H, 4.53ABq(12Hz)2H,4.56s2H, 5.15dd(5;8Hz)1H, 5.43d(5Hz)1H, 6.8-8.4m10H.

PREPARATION 5

To a solution of silver salt of 2,2,2-trichloroethylα-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate(695 mg) in hexamethyl phosphorotriamide (8 ml) is added a mixture ofcyclopropylmethyl chloroformate (480 mg) and triethylamine (180 mg), andthe mixture is stirred for 1 hour. The reaction mixture is poured intoice water, and is extracted with benzene. The extract solution is washedwith water, dried, and evaporated to leave residue. Purification of theresidue by chromatography over silica gel to give 2,2,2-trichloroethylα-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-cyclopropylmethoxycarbonyloxyethylidene)acetate(650 mg). Yield: 64.4%.

The product is a mixture (ca. 4:3) of the geometric isomers of thesubstituent at position α.

IR: ν_(max) ^(CHCl).sbsp. 3440, 1785, 1720 cm⁻¹. NMR: δ^(CDCl).sbsp.30.1-1.3m10H, 2.4s3H, 4.0m3H, 4.60s2H, 4.83s2H, 5.2- 6.1m2H, 6.8-7.5m6H.

PREPARATION 6

To a solution of p-nitrobenzylα-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-methanesulfonyloxyethylidene)acetate(1.12 g) in benzene (11 ml) is added morpholine (0.26 ml) under icecooling, and the mixture is kept at 10° C. overnight. The reactionmixture is washed with water, dried, and evaporated under reducedpressure. Purification of the obtained residue (1 g) by chromatographyover silica gel (10 g) using a mixture of benzene and ethyl acetate(1:2) gives p-nitrobenzylα-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-morpholinoethylidene)acetate (602 mg). Foam.

IR: ν_(max) ^(CHCl).sbsp.3 3430, 1774, 1694br, 1604, 1150 cm⁻¹. NMR:δ^(CDCl).sbsp.3 0.22m5H, 2.27+2.40s3H, 3.43m4H, 3.77m4H, 4.02d(6.4Hz)2H,4.57s2H, 5.05-5.27m3H, 5.89d(5.4Hz)1H, 4.12-7.65m7H, 8.23d(8.4Hz)2H.

According to the method similar to that described above, followingcompounds are prepared from the corresponding methane-sulfonates:

(1) 2,2,2-trichloroethylα-[4-(benzothiazolyl)dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-.alpha.-(1-piperidinoethylidene)acetate,IR: ν_(max) ^(CHCl).sbsp.3 3440, 1773, 1690, 1600 cm⁻¹. NMR:δ^(CDCl).sbsp.3 1.68brs6H, 2.4brs3H, 3.36brs4H, 4.63m4H, 5.0-5.7m2H,6.8-8.0m10H.

(2) p-nitrobenzylα-[4-(2-benzothiazolyl)dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-piperidinoethylidene)acetate,NMR: δ^(CDCl).sbsp.3 1.63brs6H, 2.33brs3H, 3.3brs4H, 4.53s2H,5.0-5.5m4H, 6.8-8.2m14H.

Similarly, the following compounds are prepared from the correspondingchlorides:

(1) 2,2,2-trichloroethylα-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-piperidinoethylidene)acetate,IR: ν_(max) ^(CHCl).sbsp.3 3440, 1780, 1710, 1695 cm⁻¹. NMR: 0.2-1.3m5H, 1.67brs6H, 2.40 or 2.27s3H, 3.35brs4H, 3.98d(7Hz) 1H, 4.57s2H,4.73s2H, 5.13-6.07m2H., for the isomers.

(2) 2,2,2-trichloroethylα-[4-(benzothiazolyl)dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-.alpha.-(1-piperidinoethylidene)acetatecited above.

PREPARATION 7

To a solution of p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate(504 mg) in tetrahydrofuran (8 ml) are added dropwise methanesulfonylchloride (0.13 ml) and triethylamine (0.23 ml) under ice cooling. After3 hours, the mixture is evaporated to leave residue, which is dissolvedin methylene chloride, washed with water, dried over magnesium sulfate,and evaporated. Purification of the residue by chromatography oversilica gel containing 10% water (15 g) using a mixture of benzene andethyl acetate (5:1) gives p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate(353 mg). Colorless foam.

The product contains no geometric isomer at position α. IR: ν_(max)^(CHCl).sbsp.3 1780, 1730 cm⁻¹. NMR: δ^(CDCl).sbsp.3 2.60s3H, 3.18s3H,4.58+4.88ABq(14Hz)2H, 5.24s2H, 5.92+6.08ABq(5Hz)2H, 6.73-8.20m9H.

PREPARATION 8

To a solution of p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate(940 mg) in dimethylformamide containing 10% tetrahydrofuran (5 ml) isadded toluene-p-sulfonyl chloride (456 mg). After cooling to -70° C.,the solution is mixed with triethylamine (0.3 ml). The reaction mixtureis allowed to warm slowly up to room temperature, poured into water, andextracted with ethyl acetate. The extract solution is washed with water,dried, and evaporated. The obtained residue is chromatographed oversilica gel containing 10% water using benzene containing 5% ethylacetate to give p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-toluene-p-sulfonyloxyethylidene)acetate(644 mg).

IR: ν_(max) ^(CHCl).sbsp.3 1785, 1735 cm⁻¹. NMR: δ^(CDCl).sbsp.32.45s3H, 4.75+4.20ABg( 14 Hz)2H, 5.15s2H, 5.77s2H, 8.30-6.60m13H.

PREPARATION 9

To a solution of p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonylethylidene)acetate(298 mg) in benzene (3 ml) is added morpholine (0.095 ml) at 7° to 10°C. After 130 minutes, the reaction mixture is filtered to give filtrate,which is poured into iced water, and is extracted with methylenechloride. The extract solution is washed with water, dried overmagnesium sulfate, and evaporated to give p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)-acetate(284 mg). Foam. Yield: 97.1%.

The product is a mixture (ca. 1:1) of the geometric isomers at thesubstituent on position α.

IR: ν_(max) ^(CHCl).sbsp.3 1768, 1685, 1612, 1603 cm⁻¹. NMR:δ^(CDCl).sbsp.3 1.90s1H, 2.42s1H, 3.17-3.43m4H, 3.52-3.83m4H, 4.87s2H,5.21s2H, 5.58-6.00m2H, 6.80-8.22m9H.

PREPARATION 10

To a solution of 2,2,2-trichloroethylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate(1.52 g) in benzene (30 ml) is added morpholine (0.48 ml) at beneath 10°C. After stirring for 1 hour, the mixture is washed with water, dried,and evaporated. Purification of the obtained residue by chromatographyover silica gel gives 2,2,2-trichloroethylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate(0.76 g). Yield: 50%.

The product is a mixture of isomers at substituent on position α.

NMR: δ^(CDCl) 3 1.88+2.42s3H, 3.1-3.9m8H, 4.73ABq(12Hz)2H, 4.95s2H,5.7-6.2m2H, 6.8-7.5m5H.

PREPARATION 11

To a stirred solution of p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate(500 mg) in tetrahydrofuran (20 ml) are added dropwise methylchloroformate (200 mg) and triethylamine (216 mg) under ice cooling.After 1 hour, the reaction mixture is poured into ice water, and isextracted with ethyl acetate. The extract solution is washed with water,dried, and evaporated to give p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methoxycarbonyloxyethylidene)acetate(546 mg). Foam. Yield: 97%.

The product is a mixture (ca. 2:1) of the geometric isomers at positionα.

IR: ν_(max) ^(CHCl).sbsp.3 1783, 1732, 1642, 1612, 1600 cm⁻¹.

NMR: δ^(CDCl).sbsp.3 1.95s1H, 2.47s2H, 3.68s1H, 3.80s2H,4.54+4.86ABq(14Hz) (4/3H, 4.86s2/3H, 5.25s3H, 5.73-6.03m2H,6.70-8.16m9H.

PREPARATION 12

To a solution of 2,2,2-trichloroethylα-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-hydroxyethylidene)-acetate(450 mg) in methylene chloride (7 ml) are added methanesulfonyl chloride(0.093 ml) and triethylamine (0.48 ml) at -25° C., and the mixture iskept at the same temperature for 40 minutes. To the produced solution of2,2,2-trichloroethylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-methanesulfonyloxyethylidene)acetateis added dropwise morpholine (0.112 ml), and the mixture is stirred for1.3 hours. The reaction mixture is washed with water, dried, andevaporated to give residue which is purified by chromatography oversilica gel containing 10% water to give 2,2,2-trichloroethylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-morpholinoethylidene)acetate(205 mg).

The product is a mixture (ca. 1:1.6) of the geometric isomers atposition α.

NMR: δ^(CDCl).sbsp.3 1.67s+2.35s[3H], 2.83-4.00m8H, 2.31s2H, 4.45+4.88q(12Hz): 4.47+4.83q(12Hz)[2H], 5.60-6.12m2H, 7.22s+7.23s[5H].

PREPARATION 13

To a solution of p-nitrobenzylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-methanesulfonyloxyethylidene)acetate(609 mg) in methylene chloride (3 ml) is added morpholine (0.2 ml) at-15° C., and the mixture is stirred for 50 minutes at the sametemperature. The reaction mixture is poured into ice water, and isextracted with methylene chloride. The extract solution is washed withwater, dried, and evaporated. Purification of the obtained foam (569 mg)by chromatography over silica gel (25 g) gives from the fractions elutedwith a mixture of benzene and ethyl acetate (2:1) p-nitrobenzylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-morpholinoethylidene)acetate(452 mg). Yield: 75.5%. Foam.

The product contains no geometric isomers at position α. IR: ν_(max)^(CHCl).sbsp.3 1778, 1695, 1615 cm⁻¹. NMR: δ^(CDCl).sbsp.3 2.37s3H,3.00-3.73m8H, 3.86s2H, 5.20s3H, 5.73+5.88ABq(5Hz)2H, 7.15-8.28m9H.

These products are also novel and representable by the followingformulae: ##STR21## wherein R, B, R, R', and X are as defined above; Y'is a carbonic acyloxy containing up to 12 carbon atoms, disubstitutedamino containing 2 to 20 carbon atoms, or aromatic or aliphatic sulfonylcontaining 1 to 20 carbon atoms.

Preferable groups for ABN- are phthalimido, phenoxyacetamido, andphenylacetamido; for X are a methyl, benzyl, p-nitrobenzyl, benzhydryl,and 2,2,2-trichloroethyl; for R are tertiary butoxycarbonyl,cyclopropylmethoxycarbonyl, carbobenzoxy, methoxymethyl,o-nitrophenylthio, and benzothiazol-2-ylthio; for Y' arecyclopropylmethoxycarboxy, carbobenzoxy, methoxycarboxy, alkyleneaminocontaining from 4 to 8 carbon atoms, morpholin-4-yl, dialkylaminocontaining from 2 to 6 carbon atoms, alkanesulfonyloxy containing from 1to 12 carbon atoms, or arylsulfonyloxy containing from 4 to 20 carbonatoms; and for R' are benzyl and phenoxymethyl.

The compound (9) or (10) where Y is disubstituted amino can be preparedby following reactions in conventional procedures, as shown inPreparations cited above: ##STR22## wherein A, B, R, X, and broken lineare as defined above, at about -30° C. to 0° C.

The process can be carried out in one pot, namely it is unnecessary toisolate intermediates and to remove reaction solvents for any step togive the enamine compound.

The preparation of enamines by above process and halogenation (1),deprotection of thiol (2), and cyclization (3) can also be carried outin one pot, namely without isolating any intermediate, or even removingany solvent during reaction, giving up to 80% or more of the cephemcompound (4) from the compound (9) or (10) where Y is a hydroxy. Inother words, the reaction can be carried out as simply as one reaction.In this case the solvent is selected from that suitable for allreactions. Typical examples are ether solvents (e.g. tetrahydrofuran,tetrahydropyran, and dioxan), amide solvents (e.g. dimethylformamide,dimethylacetamide, and hexamethylphosphorotriamide), and halohydrocarbonsolvents (e.g. chloroform, methylene chloride, and dichloroethane).

As stated above, this invention provides the higher yielding and simplerprocess from less expensive penicillins to give valuable keyintermediates, the 3-hydroxy-3-cephem compounds.

Another aspect of this invention is oxidative cleavage of unsaturatedbond represented by the reaction scheme: ##STR23## wherein A, B, R and Xare as defined above.

The process is carried out by subjecting the said starting materials atthe unsaturation in the substituent at position α to the oxidativecleavage to give the objective compounds.

For the oxidative cleavage are used ozone-oxidation: osmium tetroxide,hydrogen, peroxide-osumium tetroxide, sodium chlorate-osmium tetroxide,permanganates, to make glycol grouping, followed by glycol cleavage; andother oxidative cleavage, under condition where the other part of themolecule does not suffer unfavourable reactions, according toconventional methods.

Especially, ozone oxidation accompanies less side reactions, and it ispreferable for its mild reaction condition. Ozone oxidation can becarried out by introducing ozone sufficient to form ozonide to asolution of the starting materials, followed by the action of reducingreagent capable of cleaving reductively the formed ozonide. Especiallypreferable solvents are alkane, haloalkane, ether, alkanoate ester,alkanoic acid, alcohol, aromatic hydrocarbon, solvents particularly amixture of chloroalkane solvents and alcohol e.g. methanol, ethanol. Thereducing reagents can be metal and acid (zinc and acetic acid, iron andhydrochloric acid, etc.), sulfur dioxide or sulfite (sodium sulfite,potassium hydrogen sulfite, etc.), trivalent phosphorous compound(phosphite ester, phosphite salt, etc.), ferrocyanide, sulfide (dialkylsulfide e.g. dimethylsulfide, aromatic sulfide e.g. diphenyl sulfide,dibenzyl sulfide), hydrogen (in the presence of Raney nickel, platinum,palladium, etc.), borohydrides or their complex (sodium borohydride,etc.), aluminum hydride complex (lithium aluminum hydride, (etc.),hydrazine, and other reducing reagents. Formation of ozonide proceeds ata temperature lower than -80° C. or higher than room temperature,however, at lower temperature, efficacy of ozone is high and sidereaction can be surpressed. Excess ozone can be removed from reactionmedium by introduction of oxygen, nitrogen, air etc., to the reactionmixture. The reducing reagents can be added to the reaction mixturecontaining ozonide as it is or after suitable concentration of themixture. The reaction with the reducing reagent can be carried out underconventional condition suitable for the used reagents.

Ozonization stated above can be replaced by subjecting the ozonide tohydrolysis, oxidation, termal decomposition, etc. to give objectivecompounds.

Following Examples illustrate the embodiments of this invention, butthey shall not be taken to limit the scope thereof. The descriptions ofthe double bond linked to position 3 imply the presence of the positionisomer with respect to the double bond linked to position 3.

PART I. HALOGENATION Example 1. -- I

One dissolves p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate(939 mg) in tetrahydrofuran (14 ml), cools to -40° C., addstriethylamine (0.67 ml) and methanesulfonyl chloride (0.187 ml), stirsfor 30 minutes at -40° C. and for 30 minutes at 0° C. To this solution,one adds morpholine (0.209 ml), stirs for 2 hours at 0° C., addsN-bromosuccinimide (393 mg), stirs for 1.5 hours at 0° C., dilutes withwater (100 ml) and extracts with ethyl acetate. The obtained extract iswashed with water, dried over sodium sulfate, and evaporated to givefoam (1.349 g) which is purified by chromatography over silica gelcontaining 10% water to give p-nitrobenzylα-[3-phenoxymethyl-7-oxo-α-4-thia-2,6-diazabicyclo[3,2,0]hept2-en-6-yl]-α-methanesulfonyl-α-acetylacetate(81.7 mg; Yield: 7.5%), p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholino-2-bromoethylidene)acetate(956.8 mg; 77.5%), and p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate(120.5 mg; Yield: 11.2%).

Example 2.--I

One dissolves p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate(940 mg) in dichloromethane (14 ml), cools to -25° C., addstriethylamine (0.61 ml) and methanesulfonyl chloride (0.17 ml), andstirs for 1.5 hours. To the solution, one adds morpholine (0.209 ml),keeps at -25° C. for 1.5 hours, adds bromine (2.2 mmol) dissolved incarbon tetrachloride (2.2 ml) and after 30 minutes at -25° C., adds 5%aqueous sodium hydrogen carbonate, washes with water, dries andevaporates. Purification of the obtained residue (1.134 g) bychromatography over silica gel containing 10% water (100 g) using amixture of benzene and ethyl acetate (3:1 ) gives p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholino-2-bromoethylidene)acetate(852.6 mg; 69%) and p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-methanesulfonyl-α-acetylacetate(1332.2 mg; 12.2%).

Example 3.--I

One dissolves p-nitrobenzylα-[4-methoxymethylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-.alpha.-(1-hydroxyethylidene)-acetate(1.06 g) in tetrahydrofuran (10 ml), cools to -40° C. under nitrogenatmosphere, adds triethylamine (489 mg) dissolved in tetrahydrofuran (1ml) and methanesulfonyl chloride (252 mg) dissolved in tetrahydrofuran(1 ml), and stirs for 30 minutes at -40° C. and for 45 minutes at 0° C.To this solution, one adds morpholine (209 mg) dissolved intetrahydrofuran (1 ml), keeps at 0° C. for 2 hours, addsN-bromosuccinimide (392 mg), keeps at 0° C. for 1.5 hours, adds water,and removes the separated oily material, and extracts with ethylacetate. The extract solution and the removed oily material is combined,dried over magnesium sulfate, and evaporated. Purification of theobtained residual oil (1.4 g) by chromatography over silica gelcontaining 5% water (20 g) gives p-nitrobenzyl α-[4-methoxymethylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-α-(1-morpholino-2-bromoethylidene)acetate(700 mg; Yield: 52%) and p-nitrobenzylα-[4-methoxymethylthio-3-phenoxyacetamido-2-oxo-acetidin-1-yl].alpha.-(1-morpholinoethylidene)acetate(170 mg; Yield: 14%).

Stirring of the former product (100 mg) with 10% hydrochloric acid (0.3ml) in a mixture of methanol (2 ml) and tetrahydrofuran (1 ml) at 0° C.for 90 minutes, followed by isolation by diluting with water,evaporating, dissolving in chloroform, washing with water, drying overmagnesium sulfate, and evaporating gives p-nitrobenzylα-[4-methoxymethylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-.alpha.-(1-hydroxy-2-bromoethylidene)acetate(70 mg). Yield: 78%.

Example 4.--I

One dissolves p-nitrobenzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(H-hydroxyethylidene)acetate (827mg) in methylene chloride (10 ml), cools to -20° C., adds a solution ofmethanesulfonyl chloride (1M in methylene chloride; 2.2 ml) and asolution of triethylamine (1M in methylene chloride: 2.2 ml), stirs for90 minutes, cools to -25° C., adds morpholine (0.35 ml), stirs for 65minutes, adds N-bromosuccinimide (340 mg), and stirs for 1 hour. Onewashes the reaction mixture with water, dries over magnesium sulfate,and evaporates. Purification of the obtained residue by chromatographyover silica gel containing 10% water (30 g) gives p-nitrobenzylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-morpholino-2-bromoethylidene)acetate(710 mg). Yield: 65%.

    TABLE I (No. 1)      ##STR24##      Reac-  Brominat-   Reaction (2) tion (1) ing rea- Solvent Additive     (Temp.) Crop. Yield No. R.sup.1 R.sup.2 R.sup.3 X (mg) gent (mg) (ml)     (mg) (Time) (mg) (%)                    1      ##STR25##      ##STR26##      CH.sub.3      ##STR27##      463 NBS250 CCl.sub.430 ABINcat. refl.6 hr. 452 2      ##STR28##      ##STR29##      CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR30##      690 NBS195 CHCl.sub.37 ---- rt.1 hr. 670      87 3     ##STR31##      ##STR32##      CHCl.sub.3      ##STR33##      446 NBS135 CHCl.sub.330 ----  rt.; 0° C.30 min. 393  78.6 4      ##STR34##      ##STR35##      CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR36##      602 NBS181 CH.sub.2 Cl.sub.26 ---- 0°      C.2 hr. 672 100 5     ##STR37##      ##STR38##      CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR39##      172 Br.sub.218.5 CH.sub.2 Cl.sub.22 C.sub.6 H.sub.5 N20 -20°     C.15 min. 193 100 (3:2 mixture)             6      ##STR40##      ##STR41##      CH.sub.2      CCl.sub.3     ##STR42##      200 NBS50 CH.sub.2 Cl.sub.26 ---- -60° C.2 hr. 209  94 7      ##STR43##      ##STR44##      CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR45##      134 NBS33 CH.sub.2 Cl.sub.26 ---- -50° C.40 min.  97  66        8      ##STR46##      CH.sub.2      CCl.sub.3     ##STR47##      762 NBS278 CHCl.sub.340 ---- 0° C.1 hr. 537      61.6 9     ##STR48##      CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR49##      234 NBS85 CHCl.sub.33 ---- rt.80 min. 166      62 10     ##STR50##      CH.sub.2      CCl.sub.3     ##STR51##      200 NBS80 CHCl.sub.310 ---- 0° c.30 min. 177      50 11     ##STR52##      CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR53##      312 Br.sub.240 THF + CCl.sub.42 + 0.5 LHDS1.4 mmol -78° C.1 hr.     23 12      ##STR54##      CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR55##      494 Br.sub.2 40 THF + CCl.sub.48.6 + 0.96 LHDS1.8 mmol -78° C.40     min. 197     (In the Table I, ABIN is for azobisisobutyronitrile; cat. is for catalyti     amount; hr. is for hour; min. is for minutes; NBS is for     N-bromosuccinimide; refl. is for reflux; rt. is for room temperature; THF     is for tetrahydrofuran; and LHDS is for lithium hexamethyldisilazane)

    TABLE II      ##STR56##      Com-        pound(Numbers in parentheses show No. R.sub.1 R.sub.2     R.sub.3 X mp (°C.) IR:(v.sub.max.sup.CHCl.sbsp.3 cm.sup.-1)     NMR(δ.sup.CDCl.sbsp. 3) coupling constants: Hz)       (No.1)       1      ##STR57##      ##STR58##     CH.sub.3      ##STR59##     137-140°      C. 1800,1795,1740. 0.05-1.60mlOH,3.80-4.30m4H,3.90s+3.98s3H,4.50+4.72ABq     (10)1H,4.92s1H,5.95d(5)1H,6.25d(5)1H,7.68j4H. 2      ##STR60##      ##STR61##     CH.sub.2 C.sub.6      H.sub.4 NO.sub.2     ##STR62##     Foam 3400,1782,1720-1680. 3.00-3.50m4H,3.50-3.9Cm4H,4.38s2H,4.47s2H,5.005     .34m5H,5.50d(5)+5.77d(5)1H[Ca 3:2],6.70-8.25m15H. 3      ##STR63##      ##STR64##     CH.sub.2      COl.sub.3     ##STR65##     -- 3440,1780,1700,1550,1150. 0.2-1.3m5H,1.72brs6H,3.38brs4H,3.98d(12)2H,4     .55s2H,4.75s2H,4.33-4.70m2H,5.17-5.58m1H,5.72d(5)+5.92d(6)1H,6.80-7.53m6H     . 4      ##STR66##      ##STR67##     CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR68##     YellowFoam 3426,1779,1695,1603,1145. 0.23-1.27m5H,3.16-3.59m4H,3.74-3.94m     4H,4.05d(6)2H,4.50-4.71m4H,5.07-5.40m3H,5.80dd(10.5)1H,6.82-8.33m9H.5      ##STR69##      ##STR70##     CH.sub.2 C.sub.6 H.sub.4 NO.sub.2 OH -- 3426,1781,1710-1690,1601,1148.     0.23-1.27m5H,4.01d(7)2H,4.27+4.33d2H,4.55s2H,5.10-5.35m3H,5.88d(5)1H,6.83     -7.64m7H,8.22d(9)2H. 6      ##STR71##      ##STR72##     CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR73##     -- 3440,1780,1695,1600. 1.67brs6H,3.33brs4H,4.5m4H,5.0-5.5m4H,6.8-8.2m14H     . 7      ##STR74##      ##STR75##     CH.sub.2      CCl.sub.3     ##STR76##     -- 3440,1781,1698,1660. 1.68brs6H,3.38brs4H,4.4-4.9m6H,5.0-5.8m2H,6.88.2m     1OH.        8      ##STR77##     CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR78##      Oil 1795,1700. 2.50s3H,4.22+4.71ABq(14)2H,4.81s2H,5.19s2H,5.75s2H. 9      ##STR79##     CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR80##     Foam 1785,1732,1600,1172. 0.30-1.07m5H,3.88-4.78m6H,5.27s2H,5.97d2H,6.77-     7.53m7H,8.17d2H.      10     ##STR81##     CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR82##     Yellow oil 1775,1690. 3.30m4H,3.73m4H,4.50+4.95ABq(14)2H,4.87s2H,5.25s2H,     5.75+5.96ABq(4)2H,6.66-8.23m9H.(No.2)      18     ##STR83##     CH.sub.2      CCl.sub.3     ##STR84##     -- 1780,1700,1550. 3.05-3.95m8H,4.67ABq2H,4.78ABq2H,4.952H,5.83-6.15m2H,6     .82-7.48m5H.      19     ##STR85##      CH.sub.2      CCl.sub.3     ##STR86##      -- 1780,1700,1615,1600,1550. 2.85-3.25m4H,3.25-3.82m4H,3.89s2H,4.29-5.02     m4H,5.72-5.92m2H,7.25s5H.      20     ##STR87##     CH.sub.2 OCH.sub.3 CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR88##     -- 3425,1770,1693,1600. 3.21s3H,3.39m4H,3.37m4H,4.4-4.7m6H,5.2-5.5m4H,6.8     -8.3m1OH.      21     ##STR89##     CH.sub.2 OCH.sub.3 CH.sub.2 C.sub.6 H.sub.4      NO.sub. 2 OH -- 3425,1775,1694,1660. 3.43s3H,4.30s2H,4.5-4.7m4H,5.2-5.5m     4H,6.8-8.3m1OH,12.251/2H.      22     ##STR90##     CH.sub.2 C.sub.6 H.sub.4      NO.sub.2     ##STR91##     -- 1774,1695,1605. 3.34m4H,3.69m4H,4.59+4.87ABq(14)2H,4.83s2H,5.23s2H,5.7     7+6.00ABq(4)2H,6.80-8.20m9H.  Chlorination

Example 5.--I

One dissolves an azetidineacetic acid derivatives (1) in a solvent, ifrequired adds an additive, adds a brominating reagent, and lets reactfor given time at given temperature. One washes the solution with water,dries, and evaporates.

Purification of the obtained residue by chromatography over silica gelcontaining 10% water, and evaporation of the fractions containing theobjective compound gives the brominated azetidineacetic acid derivative(2).

The reaction conditions are given in TABLE I, and the physical constantsare given in TABLE II.

Example 6.--I

In a procedure similar to these described in Examples 1 to 5, thefollowing compounds are prepared:

(1) p-nitrobenzylα-[4-cyclopropylmethoxycarbonylthio-3-thienylacetamido-2-oxo-azetidin-1-yl]-α-(1-morpholino-2-bromoethylidene)acetate.

(2) 2,2,2-trichloroethylα-[4-methylsulfonylethylthio-3-carbobenzoxyamino-2-oxo-azetidine-1-yl]-α-(1-piperidino-2-bromoethylidene)acetate.

(3) phenacylα-[4-ethoxycarbonylmethylthio-3-(2,2,2-trichloroethoxycarbonyl)amino-2-oxo-azetidine-1-yl]-α-(1-morpholino-2-bromoethylidene)acetate;

(4) sodiumα-[4-isobutyrylthio-3-(o-nitrophenylsulfenyl)amino-2-oxo-azetidin-1-yl]-α-(1-acetoxy-2-bromoethylidene)acetate;

(5) pivaloyloxymethyl α-[4-benzoylthio-3-(N-tertiarybutoxycarbonyl-α-phenylglycinamido)-2-oxo-azetidin-1-yl]-α-(1-dimethylamino-2-chloroethylidene)acetate;

(6) 2,2,2-trichloroethylα-[4-chloroacetylthio-3-(N-trichloroethoxycarbonyl-α-phenylglycinamido)-2-oxo-azetidine-1-yl]-α-(1-chloro-2-bromoethylidene)acetate;

(7)α-[4-benzylthio-3-(2,2-dimethyl-4-phenyl-5-oxoimidazolidin-1-yl)-2-oxo-azetidin-1-yl]-α-(1-methoxy-2-bromoethylidene)aceticacid;

(8) 2,2,2-trichloroethylα-[4-anilinothio-3-(o-hydroxybenzylidene)amino-2-oxo-azetidine-1-yl]-α-(1-diphenylphosphinyl-2-bromoethylideneacetate;and

(9)α-[3-methyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-chloro-2-bromoethylidene)aceticacid diisopropylhydrazide;

Example 7.--I

One dissolves p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl-α-(1-hydroxyethylidene)acetate (940 mg) in tetrahydrofuran (14 ml),adds triethylamine (0.61 ml) and methanesulfonyl chloride (0.172 ml),and stirs for 1 hour ε⁺ -15° to -20° C. To the produced solution ofp-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate,one adds morpholine (0.209 ml), stirs for 1.5 hours at -15° to -20° C.,and for 2 hours at 0° C., to give a solution of p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate,cools to -15° C., adds pyridine (0.174 ml) followed by after 5 minutes asolution of bromine in carbon tetrachloride (1 mole/liter: 2.1 ml),stirs for 15 minutes at the same temperature, pours into water (50 ml),and extracts with ethyl acetate (50 ml). The extract solution is washedwith water, dried over magnesium sulfate, and evaporated to give residue(1.7 g). Purification of the residue by chromatography over silica gelcontaining 10% water gives from the fractions eluted with a mixture ofbenzene and ethyl acetate (2:1) p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethylidine)acetate(1.109 g; Yield: 89.7%) and p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethyl)-α-methanesulfonylacetate(85 mg; Yield: 7.7%).

Similar reaction using N,N-dimethylformamide (14 ml) in place oftetrahydrofuran gives the same products (910 mg; 73.6% and 100 mg; 9.0%respectively).

Example 8.--I

One suspends p-nitrobenzylα-[3-benzyl-7-oxoethylidene)-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylideneacetate(2.265 g) in anhydrous tetrahydrofuran (30 ml), adds dropwise a solutionof triethylamine (1.11 g) and methanesulfonyl chloride (630 mg) intetrahydrofuran (2 ml) at 1° to 2° C., and stirs for 25 minutes. To theproduced solution of p-nitrobenzylα-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-methanesulfonyloxyethylidene)acetate,one adds a solution of morpholine (480 mg) in tetrahydrofuran (2 ml),and stirs for 15 minutes to give a solution of p-nitrobenzylα-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-morpholinoethylidene)acetate,cools to -20° C., adds pyridine (396 mg) and a solution of bromine incarbon tetrachloride (1 mole/liter: 5 ml), pours into dilutedhydrochloric acid after 15 minutes, and extracts with ethyl acetate. Theextract solution is washed with water, dried over magnesium sulfate, andevaporated. Purification of the obtained residue by chromatography oversilica gel (50 g), from the fraction eluted with a mixture of benzenecontaining 10% ethyl acetate gives p-nitrobenzylα-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.(2-bromo-1-morpholinoethylidene)acetate(2.36 g). Yield: 78%.

The product without isolation from the solution can be diluted with 5%hydrochloric acid (10 mole equivalents) and methanol, and stirred atroom temperature for 3 hours to give p-nitrobenzyl7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate in more than 70%yield.

Example 9.--I

One dissolves diphenylmethylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-hydroxyethylidene)acetate(4.84 g) in tetrahydrofuran (60 ml), cools to -20° C., addstriethylamine (2.84 ml) with stirring, adds dropwise methanesulfonylchloride (0.82 ml) to the yellow solution, and lets react for 30minutes. To the produced solution of diphenylmethylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-methanesulfonyloxyethylidene)acetate,one adds morpholine (0.96 ml) at -40° C., stirs for 3.5 hours, addspyridine (0.77 ml) to the produced solution of diphenylmethylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicylo[3,2,0]hept-2-en-6-yl].alpha.-(1-morpholinoethylidene)acetate,cools to -40° C., adds bromine (0.49 ml), and stirs for 30 minutes, togive diphenylmethylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]α-(2-bromo-1-morpholinoethylidene)acetate. To this solution, one addsdropwise 5% hydrochloric acid (72 ml) and methanol (60 ml), stirs for 3hours at room temperature, and keeps in a refrigerator overnight. Thereaction mixture is evaporated to give residue which is dissolved inmethylene chloride, washed with water, dried over sodium sulfate, andevaporated. Purification of the obtained residue (5.83 g) bychromatography over silica gel containing 10% water (150 g) gives fromthe fraction eluted with a mixture of benzene and ethyl acetate (4:1)diphenylmethyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (3.51g) by recrystallization from n-hexane. m.p. 93°-96° C. Yield: 70%. IR:ν_(max) ^(CHCl).sbsp.3 3410, 1782, 1674, 1610 cm⁻¹. NMR: ε^(CDCl).sbsp.33.20s2H, 3.64s2H, 4.97d(4Hz)1H, 5.66dd(9:4)1H, 6.77d(9Hz)1H, 6.90s1H,7.35ml5H.

Example 10.---I

One dissolves p-nitrobenzylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-morpholinoethylidene)acetate(452 mg) in methylene chloride (5 ml), adds N-bromosuccinimide (170 mg)at -20° C., stirs for 80 minutes, pours the solution into ice water, andextracts with methylene chloride. The extract solution is washed withwater, dried over magnesium sulfate, and evaporated. Purification of theobtained residue (461 mg) by chromatography ever silica gel (25 g) givesfrom the fraction eluted with a mixture of benzene and ethyl acetate(2:1) p-nitrobenzylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0hept-2-en-6-yl]-.alpha.-(2-bromo-1-morpholinoethylidene)acetate(289 mg). Yield: 54.5%. IR: ν_(max) ^(CHCl).sbsp.3 1770, 1690, 1610cm⁻¹. NMR: δ^(CDCl).sbsp.3 3.00-3.74m8H, 5.52s2H, 4.47+4.71 ABq(13Hz)2H,5.23s2H, 5.68d(4Hz)1H, 5.94 d(4Hz)1H, 7.20-8.25m9H.

                                      TABLE II                                    __________________________________________________________________________     ##STR92##                                                                                                                       Reac-                                                                             (6)                    Reac-                        Sol-                  tion                                                                              Crude                                                                             Com-               tion                                                                             (5)                       vent       Acid       Time                                                                              Crop                                                                              pound              No.                                                                              R.sup.1                                                                             R.sup.2 R.sup.3  (mg)                                                                             (ml)       (ml)   Temp.                                                                             (min)                                                                             (mg)                                                                              No.                __________________________________________________________________________    1  PhOCH.sub.2                                                                          ##STR93##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      200                                                                              CH.sub.2 Cl.sub.2 (CH.sub.3).sub.2 CO                                                 4 4                                                                              30% HClO.sub.4  0.8                                                                  rt  50  214 1                  2  PhOCH.sub.2                                                                          ##STR94##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      200                                                                              CH.sub.2 Cl.sub.2 (CH.sub.3).sub.2 CO                                                 4 6                                                                              40% TsOH 0.5                                                                         rt  60  203 1                  3  PhCCH.sub.2                                                                          ##STR95##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      200                                                                              CH.sub.2 Cl.sub.2 (CH.sub.3).sub.2 CO                                                 4 10                                                                             30% H.sub.3 PO.sub.                                                                  rt1.0                                                                             330  35 1                  4  PhOCH.sub.2                                                                          ##STR96##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      200                                                                              THF     5  2NHCl 1.0                                                                            rt  50  105 1                  5  PhOCH.sub.2                                                                          ##STR97##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      200                                                                              CH.sub.2 Cl.sub.2 (CH.sub.3).sub.2 CO                                                 4 10                                                                             30% CF.sub.3 COOH 1.0                                                                rt  240 125 1                  6  PhOCH.sub.2                                                                          ##STR98##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      227                                                                              C.sub.6 H.sub.4 CH.sub.3 COOC.sub.2 H.sub.5                                           2 2                                                                              5% (COOH).sub.2  4.0                                                                 70° C.                                                                     30   10 6                  7  PhOCH.sub.2                                                                          ##STR99##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      200                                                                              CH.sub.2 Cl.sub.2 (CH.sub.3).sub.2 CO                                                 4 4                                                                              30% HClO.sub.4  0.8                                                                  rt  35  220 2                  8  PhOCH.sub.2                                                                          ##STR100##                                                                           CH.sub.2 CCl.sub.3                                                                     293                                                                              CH.sub.2 Cl.sub.2 (CH.sub.3).sub.2 CO                                                 5 5                                                                              30% HClO.sub.4  1.0                                                                  rt  30  310 3                  9  PhOCH.sub.2                                                                          ##STR101##                                                                           CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      221                                                                              THF     5  30% HClO.sub.4  0.5                                                                  rt  45  231 4                  10 PhOCH.sub.2                                                                         H       C(CH.sub.3).sub. 3                                                                     200                                                                              THF     5  30%    rt  15  226 5                                                          HClO.sub.4                                                                    1.0                                   11 PhOCH.sub.2                                                                          ##STR102##                                                                           CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      227                                                                              CH.sub.2 Cl.sub.2 (CH.sub.3).sub.2 CO                                                 4 4                                                                              30% HClO.sub.4  0.8                                                                  rt  15  192 6                  12 PhCH.sub.2                                                                           ##STR103##                                                                           CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      200                                                                              THF     5  30% HClO.sub.4  0.5                                                                  rt  30  221 7                  __________________________________________________________________________     Ph is for phenyl;                                                             THF is for tetrahydrofuran;                                                   rt is for room temperature;                                                   and TsOH is for toluene-p-sulfonic acid                                  

                                      TABLE IV                                    __________________________________________________________________________     ##STR104##                                                                   Compound                             (Numbers in parentheses show             No.   R.sup.1                                                                             R.sup.2                                                                            R.sup.3  m.p. IR:ν.sub.max.sup.CHCl.sbsp.3                                                     NMR: δ.sup.CDCl.sbsp.3                                                  coupling constants in                    __________________________________________________________________________                                         Hz)                                      1.    PhOCH.sub.2                                                                          ##STR105##                                                                        CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      44- 46° C.                                                                  3415,2557, 1776,1748, 1693,1517.                                                    1.93s3H,2.12d(8.5)1H,4.57s2H,4.87s1H,                                         5.03brs1H, 5.17bbr1H,5.92s2H,ca,5.5m2                                         H,6.83-8.25m1OH. [α] .sub.D.sup                                         .23 -74.2° (c=0.271,                                                   CHCl.sub.3).                             2.    PhOCH.sub.2                                                                          ##STR106##                                                                        CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      Foam 3425,2568, 1776,1692, 1522.                                                         2.13d(9)1H,2.20s3H,4.55s2H,5.30s2H,ca                                         .5.30m2H, 6.78-8.20m1OH,12.60s1H.        3.    PhOCH.sub.2                                                                          ##STR107##                                                                        CH.sub. 2 CCl.sub.3                                                                    Foam 3425,2565, 1779,1694, 1519.                                                         2.10d(9.5)1H,2.26s3H,4.90+4.55ABq(12)                                         2H,5.52- 5.05m2H,6.73-7.40m6H,11.92s1                                         H.                                       4.    PhOCH.sub.2                                                                          ##STR108##                                                                        CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      Foam 3425,2564, 1773,1726, 1693,1522.                                                    2.12d(9)1H,2.25+2.08s+s6H,4.50s2H,5.2                                         0s2H,5.35- 5.08m2H,6.70-8.10m1OH.        5.    PhOCH.sub.2                                                                         H    C(CH.sub.3).sub.3                                                                      Semisolid                                                                          3415,2550,                                                                          1.45s9H,2.00d(10)1H,4.08+3.58ABq(17)2                                         H,4.49s2H,                                                              1775,1740                                                                           5.15dd(4.5;10)1H,5.55dd(4.5;8)1H,6.70                                         -7.35m5M,                                                               1694,1513.                                                                          7.83d(8)1H.                              6.    PhOCH.sub.2                                                                          ##STR109##                                                                        CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      Foam 3400,1780, 1692,1610, 1603.                                                         2.25d(10)1H,4.25d(2)2.H,4.58s2H,5.20-                                         5.37m4H, 6.84-8.24m9H,12.1s1H.           7.    PhCH.sub.2                                                                           ##STR110##                                                                        CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      Foam 3418,2550, 1771,1747, 1678,1521.                                                    1.87s3H,2.05d(8)1H,3.58s2H,4.77s1H,4.                                         95s1H, 5.10brs1H,5.27s2H,7.10-8.12m1O                                         H,5.4m2H.                                __________________________________________________________________________

part ii. deprotection example 1.--II

To a solution of3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-ene(200 mg)in a mixture of methylene chloride (8 ml) and acetone (8 ml) is added30% perchloric acid aqueous solution (1.0 ml), and the mixture isstirred for 40 minutes at room temperature. After diluting with excesswater, the reaction mixture is extracted with methylene chloride. Theextract solution is washed with water, dried over sodium sulfate, andconcentrated. The white crystalline residue is4,3-mercapto-3β-phenoxyacetamido-2-oxoazetidine, m.p. 137°-138° C.[α]_(D) ²³ +38.0±3.0°[c=0.261, CHCl₃ +C₂ H₅ OH(4:1)]. IR: ν_(max)^(Nujol) 3290, 3200, 2562, 1757, 1658, 1549 cm⁻¹. NMR: δ^(d) 6^(-DMSO)3.17brs1H, 4.58s2H, 5.00brs1H, 5.32dd(9;5Hz)1H, 6.80-7.43m6H.

Example 2.--II

To a solution of α-[3-substituted(R¹)-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-substituted(R²)-acetic acid ester (R³) (5) in a solvent is added an acid, and themixture is stirred at specified temperature for specified time. Thereaction mixture is diluted with water, and extracted with methylenechloride. The extract solution is washed with water, dried over sodiumsulfate, and evaporated to give objective α-[4-mercapto-3-substitutedamino (R¹ CONH-)-2-oxeazetidin-1-yl]- α-substituted (R²)acetic acidester (R³) (6).

Table II shows reaction conditions, and Table IV shows the physicalconstants of the product (6). In Table II, the crude yield means weightof the products. They are almost pure when analyzed by thin-layerchromatogram and NMR-spectrum. Some of them were purified to givecrystals.

In Reactions No. 3 and 6, the objective compounds were obtained in lowyield, accompanied by a large amount of the starting materials andby-products.

Example 3.--II

To a solution of p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-isopropenylacetate(200 mg) in tetrahydrofuran (5 ml) are added oxalic acid (200 mg) andwater (0.5 ml), and the mixture is stirred at room temperature for 3hours. The chromatogram of the reaction mixture shows the presence ofp-nitrobenzylα-[4-mercapto-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-α-isopropenylacetateand the starting material.

Example 4.--II

In a procedure similar to Example 2.--II, the following compounds areprepared:

(1) 4-mercapto-3-thienylacetamido-2-oxo-1-acetylazetidine from6-acetyl-3-thienylmethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-hept-2-ene;

(2) 4-mecapto-3-benzamido-2-oxo-1-trifluoroacetylazetidine from6-trifluoroacetyl-3-phenyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-hept-2-ene

(3) 4-mercapto-3-acetamido-2-oxo-1-methylazetidine from3,6-dimethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-ene;

(4)4-mercapto-3-(α-phenyl-α-chloroacetamido)-2-oxo-1-carbethoxycarbonylazetidinefrom6-carbethoxycarbonyl-3-phenylchloromethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-ene;

(5) α-[4-mercapto-3-formamido-2-oxoazetidin-1-yl]-α-isopropylideneacetic acid fromα-[7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-isopropylideneaceticacid; and

(6)4-mercapto-3-benzylthiocarbonylamino-2-oxo-1-p-toluenesulfonylazetidinefrom3-benzylthio-6-p-toluenesulfonyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-ene.

PART III DEPROTECTION AND CYCLIZATION Example 1.--III

(1) To a solution of methylα-[4-cyclopropylmethoxycarbonylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-(2-bromo-1-cyclopropylmethoxycarbonyloxyethylidene)-acetate(500 mg) in methylene chloride (20 ml) is added aluminum chloride (510mg) at once and the mixture is stirred at room temperature. After 1hour, the mixture is poured into cold 3% hydrochloric acid (20 ml), andextracted with methylene chloride. The extract solution is washed withwater, dried over magnesium sulfate, and evaporated to give methylα-[4-mercapto-3-phthalimido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)-acetate(252 mg). Yield: 72.5%. IR: ν_(max) ^(CHCl).sbsp.3 1790, 1783, 1728,1670, 1620 cm⁻¹. NMR: δ^(CDCl).sbsp.3 1.80d(11Hz)1H, 3.87s3H,4.22+4.56AB2(10Hz)2H, 5.38dd (11; 5Hz)1H, 5.70d(5Hz)1H, 7.76m4H,12.3s1H.

(2) Methylα-[4-mercapto-3-phthalimido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)-acetate(a)is treated under following conditions to give methyl3-hydroxy-7-phthalimido-3-cephem-4-carboxylate (b): m.p. 223°-226° C.IR: ν_(max) ^(CHCl).sbsp.3 1797, 1779, 1728, 1667, 1616 cm⁻¹. NMR:δ_(max) ^(CDCl).sbsp.3 3.26+4.50ABq(14(2H), 5.60s3H, 5.63+6.15ABq(4)2H,7.16m4H.

(i) To a solution of (a) (80 mg) in benzene (8 ml) is added,N,N-dimethylaniline (20 mg), and the mixture is refluxed under nitrogenatmosphere. After 30 minutes, the reaction mixture is cooled, acidifiedwith 5% hydrochloric acid, and is extracted with ethyl acetate. Theextract solution is washed with water, dried over magnesium sulfate, andevaporated. The residue (71 mg) is mixed with ethyl acetate (1 ml) andleft for a while to give (b)(25 mg). m.p. 223°-226° C. Yield: 38.9%.

(ii) A solution of (a)(150 mg) in hexamethylphosphorotriamide (1--1) isstirred at room temperature for 1 hour. The reaction mixture is mixedwith ice water (6 ml) and ether (0.5 ml), to separate crystals of (b)(50 mg) which can be collected by filtration. Yield: 40.8%.

(iii) A solution of (a) (200 mg) is brought on the precoated PLC plate(silica gel F-254) distributed by E. Merck AG., and developed with amixture of benzene and ethyl acetate (2:1). The band of main product isextracted with ethyl acetate containing 3% methanol, and the extract isevaporated under reduced pressure. The residue is dissolved inchloroform, freed from insoluble material, and evaporated to give (b)(62 mg). Yield: 37.9%.

Methyl 3-oxo-7-phthalimidocepham-4-carboxylate (b) thus prepared byabove methods is dissolved in dioxane, mixed with a solution ofdiazomethane in ether, and stirred for 1 hour at room temperature. Thereaction mixture is evaporated under reduced pressure to give methyl3-methoxy-7-phthalimido-3-cephem-4-carboxylate in nearly quantitativeyield. Recrystallization from a mixture of acetone and ether gives purecrystals, m.p. 225°-227° C.

Example 2.--III

(1) To a solution of 2,2,2-trichloroethylα-[4-cyclopropyl-methoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-[2-bromo-1-(piperidin-1-yl)ethylidene]acetate(573 mg) in methanol (30 ml) is added 10% hydrochloric acid (7 ml), andthe mixture is stirred at room temperature or at 40° to 45° C. After 30minutes, the reaction mixture is poured into ice water, and is extractedwith benzene. The extract solution is washed with water, dried, andevaporated to give 2,2,2-trichloroethylα-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)-acetate (434 mg). Yield: 83.5%.IR: v_(max) ^(CHCl).sbsp.3 3450, 1790, 1720, 1720 (sh), 1700 cm⁻¹. NMR:δ^(CDCl).sbsp.3 0.1-1.4m7H, 3.98d(7Hz)2H, 4.27d(5Hz)2H, 4.57s1H,4.82d(3Hz)2H, 5.27d(6;8Hz)1H, 5.93d(5Hz)1H, 6.8-7.5m6H, 11.67-brs1H.

(2) To a stirred solution of 2,2,2-trichloroethylα-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidine-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate(330 mg) in methylene chloride (6 ml) is added aluminum chloride (330mg) at room temperature, and the mixture is stirred for 60 minutes. Thereaction mixture is poured into ice cold diluted hydrochloric acid, andis extracted with ethyl acetate. The extract solution is washed withdiluted hydrochloric acid and water, dried, and evaporated to give2,2,2-trichloroethyl 7-phenoxyacetamido-3-oxocepham-4-carboxylate (300mg). Foam. IR: v_(max) ^(CHCl).sbsp.3 3420, 1780, 1685 cm⁻¹. NMR:δ^(CDCl).sbsp.3 3.37s2H, 4.53s2H, 4.85s2H, 5.07d(4)1H, 5.20-5.73m2H,6.8-7.7m6H.

Example 3. --III

By a method similar to that described in Example 2.--III (1),2,2,2-trichloroethylα-[4-carbobenzoxythio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-[2-bromo-1-(piperidin-1-yl)ethylidene]acetateis hydrolyzed in methanolic hydrochloric acid to give2,2,2-trichloroethylα-[4-carbobenzoxythio-3-phenoxyacetamido-2-oxoazetidino-1-yl]-.alpha.-(2-bromo-1-hydroxyethylidene)acetate,and the product is cyclized with aluminum chloride in methylene chlorideto give 2,2,2-trichloroethyl7-phenoxyacetamido-3-oxocepham-4-carboxylate, identical with the productof Example 2.--(III)(2).

Example 4.--III

(1) To a solution of p-nitrobenzylα-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidine-1-yl]-α-[2-bromo-1-(morpholin-4-yl)ethylidene]acetate(300 mg) in a mixture of methanol (22 ml) and methylene chloride (3.5ml), and the mixture is stirred at room temperature under nitrogenatmosphere after addition of 10% hydrochloric acid (4ml). After 2 hours,the reaction mixture is poured into ice water, and is extracted withchloroform. The extract solution is washed with water, dried, andevaporated to give p-nitrobenzyl4-cyclopropyl-methoxycarbonylthio-3-phenoxyacetamido-2-oxo-α-(2-bromo-1hydroxyethylidene)azetidine-1-acetate(252 mg). Foam. Yield: 92.8%. IR: v_(max) ^(CHCl).sbsp.3 3426, 1781,1710, 1690, 1601 cm⁻¹. NMR: δ^(CDCl).sbsp.3 0.23-1.33m5H, 3.84-4.36m4H,4.55s2H, 5.10-5.32m3H, 5.88d(5Hz)1H, 6.83-8.33m9H, 12.0s1H.

(2) To a solution of p-nitrobenzylα-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate(281 mg) in methanol free methylene chloride (2.1 ml) is added aluminumchloride (220 mg) under ice cooling, and the mixture is stirred underargon atmosphere. After 35 minutes, the reaction mixture is poured intoice water containing 4N-hydrochloric acid (4 ml). stirred for 10minutes, and is extracted with chloroform. The extract solution iswashed with water, dried and evaporated to give p-nitrobenzylα-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate(150 mg). Yellow foam. Yield: 94.6%. IR: v_(max) ^(CDCl).sbsp.3 3400,1780, 1692, 1610, 1603 cm⁻¹. NMR: δ^(CDCl).sbsp.3 2.25d(10Hz)1H,4.25d(2Hz), 4.58s2H, 5.20-5.37m4H, 6.84-8.24m9H, 12.1s1H.

(3) To a solution of p-nitrobenzylα-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)-acetate(106 mg) in benzene (5ml) is added silica gel F-254 (500 mg) distributedby E. Merck Ag., and the mixture is shaken at room temperature for 1hour. The insoluble material is removed by filtration, and washedseveral times with chloroform. The filtrate and washed solution arecombined and evaporated under reduced pressure to give p-nitrobenzyl3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (60 mg). Yield:66.3%. m.p. 95.5°-99.5° C. IR: ν_(max) ^(CHCl).sbsp.3 3400, 1785, 1685,1605. NMR: δ^(CDCl).sbsp.3 2.03s2H, 4.60s2H, 5.07+5.37ABq(4)2H,5.73d(4)1H, 5.68dd(9;4)1H, 6.83-8.32m9H.

(4) A solution of p-nitrobenzylα-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)-acetate(70 mg) prepared by the method of Example 4.--III(2) in a mixture ofmethylene chloride (2 ml) and methanol (2ml) is stirred for 3 hours atroom temperature. The reaction mixture is poured into ice water, and isextracted with methylene chloride. The extract solution is washed withwater, dried over magnesium sulfate, and evaporated to givep-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (42mg), identical with the product of Example 4(3). Yield: 70%.

(5) A solution of p-nitrobenzylα-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetateprepared by the method of Example 4.--III(2) (70 mg) in a mixture ofmethylene chloride (2 ml), methanol (2ml), and 10% hydrochloric acid(0.3 ml) is stirred at room temperature for 2 hours. The reactionmixture is poured into ice water, and is extracted with methylenechloride. The extract solution is washed with water, dried overmagnesium sulfate, and evaporated to give p-nitrobenzyl3-oxo-7-phenoxyacetamidocepham- 4-carboxylate (44.5 mg), identical withthe product of Example 4.--III(3). Yield: 74%.

Example 5.--III

(1) A solution of p-nitrobenzylα-[4-carbobenzoxythio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-[2-bromo-1-(morpholin-4-yl)ethylidene]acetate(469 mg) in a mixture of methylene chloride (4 ml), methanol (4 ml), 10%hydrochloric acid (0.8 ml) is stirred at room temperature for 2 hours.The reaction mixture is diluted with ice water, and is extracted withmethylene chloride. The extract solution is washed with water, driedover magnesium sulfate, and evaporated to give p-nitrobenzylα-[4-carbobenzoxythio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate(426 mg). Yield: Quantitative. IR: ν_(max) ^(CHCl).sbsp.3 3408, 1788,1725, 1696, 1615, 1602 cm⁻¹. NMR δ^(CDCl) 3 4.27d(3Hz)2H, 4.48s2H,5.16s2H, 5.22s2H, 5.29m1H, 5.86d(5Hz)1H, 6.74-8.20m9H.

(2) To a solution of p-nitrobenzylα-[4-carbobenzoxythio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate(480 mg) in methylene chloride (5 ml) containing 20% of nitromethane isadded a solution of aluminum chloride (270 mg) in methylene chloridecontaining 20% of nitromethane (4 ml), and the mixture is stirred atroom temperature for 1 hour. The reaction mixture is poured into dilutedhydrochloric acid, and is extracted with methylene chloride. The extractsolution is washed water, dried over magnesium sulfate, and evaporatedto give p-nitrobenzylα-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate(376 mg). Yield: 99.5%.

Example 6.--III

To a solution of p-nitrobenzylα-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-[2-bromo-1-morpholin-4-yl)ethylidene]acetate(151 mg) in methylene chloride (1.5 ml) is added aluminum chloride 0.42mg), and the mixture is stirred for 50 minutes under ice cooling. Themixture is diluted with ice water (2 ml), stirred for 5 minutes, andstirred with a mixture (15 ml) of methanol and methylene chloride (5:1)after addition of 10% hydrochloric acid (3 ml) at room temperature for80 minutes. The reaction mixture is diluted with ice water, and isextracted with chloroform. The extract solution is washed with water,dried over magnesium sulfate, and evaporated to give p-nitrobenzyl3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (63 mg). Yield: 63%.This product is identical with the product of Example 4--III(3) producedby hydrolysis of the 4-morpholino group to be replaced with thecorresponding hydroxy group.

Example 7.--III

To a solution of 2,2,2-trichloroethylα-[4-(benzothiazol-2-yl)dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate(100 mg) in ethanol (10 ml) is added sodium borohydride (5 mg) at 0° C.and the mixture is for 15 minutes. The reaction mixture is neutralizedwith a few drops of glacial acetic acid and water, and is extracted withethyl acetate. The extract solution is washed with water, dried, andevaporated. The residue is dissolved in N,N-dimethylformamide (4 ml),mixed with triphenylphosphine (30 mg), stirred for 1.5 hours at roomtemperature, and diluted with ethyl acetate. This solution is washedwith water, dried, and evaporated. The resulting 2,2,2-trichloroethyl7-phenoxyacetamido-3-oxocepham-4-carboxylate is dissolved in methylenechloride (4 ml), mixed with a solution of diazomethane in ether, andstirred for 25 minutes at room temperature. The solution is evaporatedto give residue, which gives by purification by thin-layerchromatography 2,2,2-trichloroethyl7-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylate. The IR-spectrum andRf values on thin layer chromatogram of the product is identical withthese of the authentic sample prepared through other route of synthesis.

Example 8.--III

In a procedure similar to these of the preceding Examples, followingcompounds are prepared:

(1) methyl 7-phthalimido-3-hydroxy-3-cephem-4-carboxylate,

(2) 2,2,2-trichloroethyl7-phenoxyacetamido-3-(morpholin-4-yl)-3-cephem-4-carboxylate,

(3) p-methoxybenzyl7-(2,2-dimethyl-3-nitroso-4-phenyl-5-oxoimidazolidin-1-yl)-3-hydroxy-3-cephem-4-carboxylate,

(4) p-nitrobenzyl 7-N-tertiarybutoxycarbonyl-α-phenylglycyl)amino-3-oxocepham-4-carboxylate,

(5) 2,2,2-trichloroethyl7-thienylacetamio-3-hydroxy-3-cephem-4-carboxylate,

(6) p-nitrobenzyl 7-salicylideneamino-3-hydroxy-3-cephem-4-carboxylate,

(7) 2,2,2-trichloroethyl7-benzyloxycarbonylamino-3-hydroxy-3-cephem-4-carboxylate,

(8) p-nitrobenzyl7-(2,2,2-trichloroethoxycarbonyl)amino-3-hydroxy-3-cephem-4-carboxylate.

Example 9.--III

To a solution of 2,2,2-trichloroethylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-[2-bromo-1-morpholin-4-yl)ethylidene]acetate(6.00 g) in a mixture of chloroform (150 ml) and methanol (200 ml) isadded 10% hydrochloric acid (40 ml) at room temperature, and the mixtureis stirred for 60 minutes. The reaction mixture is pourd into ice water,and extracted with chloroform. The extract solution is washed withwater, dried, and evaporated to give 2,2,2-trichloroethyl3-oxo-7-phenoxyacetamidocepham-4-carboxylate (4.70 g). Foam. Yield:99.8%.

Example 10.--III

To a solution of p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-[2-bromo-1-(morpholin-4-yl)ethylidene]acetate(63 mg) in a mixture of methanol (4 ml) and methylene chloride (3 ml) isadded 10% hydrochloric acid (0.38 ml), and the mixture is stirred atroom temperature for 75 minutes. The reaction mixture is poured into icewater, and is extracted with methylene chloride. The extract solution iswashed with water, dried over magnesium sulfate, and evaporated to givep-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (41mg). m.p. 95.5°-99.5° C. Yield: 82.9%.

Example 11.--III

To a solution of p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-[2-chloro-1-(morpholin-4-yl)ethylidene]acetate(106 mg) in a mixture (6 ml) of methanol and methylene chloride (2:1) isadded 2N-hydrochloric acid (0.93 ml), and the mixture is stirred at roomtemperature under argon atmosphere. After 40 minutes, the reactionmixture is diluted with ice water, and is extracted with methylenechloride. The extract solution is washed with water, dried overmagnesium sulfate, and evaporated to give yellow oil (94 mg).Purification of the oil by chromatography over thin-layer of silica gelgives from the fraction eluted with a mixture of benzene and ethylacetate (1:2) p-nitrobenzyl3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (20 mg). Yield: 22%.

Example 12.--III

To a solution of 2,2,2-trichloroethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-[2-bromo-1-(morpholin-4-yl)ethylidene]acetate(117 mg) in a mixture (4 ml) of methanol and chloroform (1:1) is added10% hydrochloric acid (0.5 ml), and the mixture is stirred for 2 hoursat room temperature. The reaction mixture is extracted with chloroform.The extract solution is washed with water, dried, and evaporated. Thepurification of the obtained residue by chromatography over silica gelgives 2,2,2-trichloroethyl 3-oxo-7-phenylacetamido-cepham-4-carboxylate(41 mg). Yield: 44%. NMR: δ^(CDCl) 3 3.33s2H, 3.60s2H, 4.83s2H,5.00d(5)1H, 5.13-5.70m2H, 6.82d(8)1H, 7.25m5H.

Example 13.--III

To a solution of p-nitrobenzylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-[2-bromo-1-(morpholin-4-yl)ethylidene]acetate(248 mg) in a mixture of methanol (8 ml) and methylene chloride (6 ml)is added 10% hydrochloric acid (1.5 ml) under ice cooling, and themixture is stirred for 2 hours. The reaction mixture is poured into icewater, and is extracted with methylene chloride. The extract solution iswashed water, dried over magnesium sulfate, and evaporated to giveresidue (184 mg). Purification of the residue by chromatography oversilica gel containing 10% water (10 g) gives from the fraction elutedwith a mixture of benzene and ethyl acetate (2:1) p-nitrobenzyl7-phenylacetamide-3-hydroxy-3-cephem-4-carboxylate (66 mg). Oil. Yield:35%. IR: ν_(max) ^(CHCl).sbsp.3 3400, 1782, 1678, 1612. NMR:δ^(CDCl).sbsp.3 3.32d2H, 3.63s2H, 4.97d1H, 5.34dsH, 5.60q1H, 7.3m6H,7.47-8.30q4H.

Example 14.--III

In a procedure similar to these of the preceding Examples, followingcompounds are prepared:

(1) 7-acetamido-3-oxocepham-4-carboxylic acid 1,2-diisopropylhydrazide,

(2) diphenylmethyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate,and

(3) 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid.

Example 15.--III

To a solution of p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-[2-bromo-1-(morpholin-4-yl)ethylidene]acetate(580 mg) in tetrahydrofuran (10 ml) is added 60% perchloric acid aqueoussolution (1.5 ml) at -10° C., and the mixture is stirred for 30 minutes.The reaction mixture is diluted with water, and is extracted withmethylene chloride. The extract solution is washed with water, driedover anhydrous sodium sulfate, and evaporated to give pale yellow foam(512 mg). The foam is purified by chromatography over silica gelcontaining 10% water (50 g) to separate from fractions eluted with amixture of benzene and ethyl acetate (1:1) p-nitrobenzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-bromo-1-hydroxyethylidene)acetate(foam: 207 mg: yield: 40%). IR: ν_(max) ^(CHCl).sbsp.3 1781 cm⁻¹. NMR:δ^(CDCl).sbsp.3 3.75+ 3.95ABq(10Hz)2H, 4.72s2H, 5.25s2H, 5.73d(4Hz)1H,6.07d(4Hz)1H, 6.73-8.15m9H, 12.07s1H.

From the fractions p-nitrobenzylα-[3-phenoxyacetamido-4-mercapto-2-oxoazedtidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetatecan also be isolated as a by-product.

The former main product (84 mg) is dissolved in tetrahydrofuran (2 ml),mixed with 2N-hydrochloric acid (0.2 ml), and let stand at 0° C. for 30minutes and at room temperature for 1 hour. The reaction mixture isdiluted with water, and is extracted with methylene chloride. Theextract solution is washed with water, dried over sodium sulfate, andevaporated. The residue (75 mg) can be identified with p-nitrobenzyl7-phenoxyacetamido-3-oxocepham-4-carboxylate by IR- andNMR-spectroscopy.

Example 16.--III

One dissolves diphenylmethylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-hdyroxyethylidene)acetate(4.84 g) in tetrahydrofuran (60 ml), cools to -20° C., addstriethylamine (2.84 ml) with stirring, adds dropwise methanesulfonylchloride (0.82 ml) to the yellow solution, and lets react for 30minutes. To the produced solution of diphenylmethylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-methanesulfonyloxyethylidene)acetate,one adds morpholine (0.96 ml) at -40° C., stirrs for 3.5 hours, addspyridine (0.77 ml) to the produced solution of diphenylmethylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-morpholinoethylidene)acetate,cools to -40° C., adds bromine (0.49 ml), and stirs for 30 minutes togive diphenylmethylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(2-bromo-1-morpholinoethylidene)acetate. To this solution, one addsdropwise for 3 hours at room temperature 5% hydrochloric acid (72 ml)and methanol (60 ml), stirs, and keeps in a refrigerator overnight. Thereaction mixture is evaporated to give residue which is dissolved inmethylene chloride, washed with water, dried over sodium sulfate, andevaporated. Purification of the obtained residue (5.83 g) bychromatography over silica gel containing 10% water (150 g) gives fromthe fraction eluted with a mixture of benzene and ethyl acetate (4:1)diphenylmethyl 7-phenylacetamido-3hyroxy-3-cephem-4-carboxylate (3.51 g)by recrystallization from n-hexane. m.p. 93°-96° C. Yield: 70%. IR:ν_(max) ^(CHCl).sbsp.3 3410, 1782, 1674, 1610 cm⁻¹. NMR: δ^(CDCl).sbsp.33.20s2H, 3.64s2H, 4.97d(4Hz)1H, 5.66dd(9:4Hz)1H, 6.77d (9Hz)1H, 6.90s1H,7.35m15H.

Example 17.--III

One adds triethylamine (5.68 ml) to a stirred suspension ofp-nitrobenzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (9.06 g) intetrahydrofuran (120 ml) under nitrogen atmosphere at -20° C. to giveclear solution, adds methanesulfonyl chloride (1.65 ml) to the solution,stirs for 30 minutes at the same temperature, adds morpholine (1.92 ml),warms to 0° C., stirs for 5 hours, cools to -30° C. to -35° C., addspyridine (1.54 ml) and bromine (3.12 g), stirs for 20 minutes, warms toice-water temperature, adds 5% hydrochloric acid (144 ml) and methanol(120 ml), stirs for 3 hours at room temperature, and lets standovernight at 0° C. Collection of the separated crystals in the reactionmixture by filtration gives p-nitrobenzyl7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (6.678 g). m.p. 201°C. Yield: 71%.

(1) To a dry ice acetone cooled solution of diphenylmethylα-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-chloro-2-propen-2-yl)acetate(160 mg) in a mixture of methylene chloride (3.2 ml) and methanol (0.3ml) is introduced ozone until the reaction mixture shows blue color.Then excess ozone is purged with oxygen, mixed with an aqueous solutionof 95% sodium hydrogen sulfite (100 mg), warmed to room temperature todecompose the ozonide. After 1.5 hours, the solution is washed with 5%sodium hydrogen carbonate and water, dried, and concentrated to removemethylene chloride. The resultant oil (132 mg) is purified overthin-layer chromatographic plate (Merck 60F-254) using a mixture ofbenzene and ethyl acetate (1:1) as developing solvent to givediphenylmethylα-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]-hept-2-en-6-yl]-α-(2-chloro-1-hydroxyethylidene)acetate(44 mg) as glass.

IR: ν_(max) ^(CHCl).sbsp.3 1784, 1672, 1620, 1603 cm⁻¹.

NMR: δ^(CDCl).sbsp.3 4.00s2H, 4.66+4.96ABq(14Hz)2H, 5.23s2H.

(2) To an ice cooled solution of diphenylmethylα-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-chloro-1-hydroxyethylidene)acetate(36 mg) in a mixture of methanol and tetrahydrofuran (1:1) (1.1 ml) isadded 1N-hydrochloric acid (0.39 ml), warmed to the room temperature,and the mixture is stirred for 1.5 hours. The reaction mixture is pouredinto ice water, and is extracted with methylene chloride. The extractsolution is washed with 5% aqueous sodium hydrogen carbonate solutionand water, dried over sodium sulfate, and evaporated. Purification ofthe obtained residue by thin-layer chromatography using a mixture ofbenzene and ethyl acetate (3:2) gives diphenylmethyl7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate (6 mg). m.p.125°-126° C.

IR: v_(max) ^(CHCl).sbsp.3 3420, 1788, 1738, 1692, 1600 cm⁻¹.

NMR: δ^(CDCl).sbsp.3 3.33s2H, 4.54s2H, 5.02d(4Hz)1H, 5.26s2H,5.62dd(10:4Hz)1H, 6.81-7.45m10H, 11.5brs1H.

Example 18.--III

To a solution of p-nitrobenzylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-60-(2-bromo-1-dimethylaminoethylidene)acetate (380 mg) in tetrahydrofuran(10 ml) are added 5,6 sulfuric acid (2 ml) and methanol (10 ml), and themixture is stirred for 2 hours at room temperature. The reaction mixtureis kept at 0° C. overnight to separate p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (240 mg), m.p. 201° C.

                                      TABLE                                       __________________________________________________________________________     ##STR111##                                                                   Com-                                   NMR: δ.sup.CDCl.sbsp.3           pound                                  (Numbers in parentheses show           No. R.sup.1 R.sup.2   X   m.p. IR:ν .sub.max.sup.CHCl.sbsp.3                                                      coupling constants in                  __________________________________________________________________________                                           Hz)                                         ##STR112##                                                                           CH.sub.2 CCl.sub.3                                                                      OH  --   3420,1780, 1685.                                                                      3.37s2H,4.53s2H,4.85s2H,5.07d(4)1H,                                           5.20- 5.73m2H,6.8-7.7m6H.              2                                                                                  ##STR113##                                                                           CH.sub.2 C.sub.6 H.sub.4 NO.sub.2 -p                                                    OH  95.5°- 99.5° C.                                                      3400,1785, 1685,1605                                                                  2.03s2H,4.60s2H,5.07+5.37ABq(4)2H,5                                           .37d(4)1H, 5.68dd(9;4)1H,6.83-8.32m                                           9H.                                    3                                                                                  ##STR114##                                                                           CH.sub.2 C.sub.6 H.sub.4 NO.sub.2 -p                                                    OH  --   3400,1782 1678,1612.                                                                  3.32d2H,3.63s2H,4.97d1H,5.34dsH,5.6                                           0q1H,  7.3m6H,7.47-8.30q4H.            4                                                                                  ##STR115##                                                                           CH.sub.2 CCl.sub.3                                                                      OH  --   --      3.33s2H,3.60s2H,4.83s2H,5.00d(5)1H,                                           5.13- 5.70m2H,6.82d(8)1H,7.25m5H.      5                                                                                  ##STR116##                                                                           CH.sub.3  OH  223°- 226° C.                                                        1797,1779, 1728,1667, 1616.                                                           3.26+4.50ABq(14)2H,5.60s3H,5.63+6.1                                           5ABq(4)2H, 7.16m4H.                    __________________________________________________________________________

example 19.--III

To a solution of p-nitrobenzylα-[4-methoxymethylthio3-phenoxyacetamido-2-oxoacetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate(200 mg) in a mixture of dioxane (5 ml) and ethanol (2 ml) is added asolution of mercuric chloride (300 mg) in water (2 ml), and the mixtureis stirred for 12 hours at 50° C. The reaction mixture is concentratedunder reduced pressure, extracted with ethyl acetate, washed with water,dried and evaporated to give residue, which is dissolved in a mixture ofmethylene chloride and methanol, passed through a layer of silica gel,concentrated, and treated with ether. The obtained foam is p-nitrobenzyl7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate identical withauthentic sample.

Example 20.--III

One adds to a solution of benzylα-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-hydroxyethylidene)acetate(1.424 g) in tetrahydrofuran (15 ml), triethylamine (0.96 ml), andmethanesulfonyl chloride (0.28 ml) at -30° to -20° C., stirs for 55minutes to give benzylα-[3-benzyl-7-oxo4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-methanesulfonyloxyethylidene)acetate,adds morpholine (0.40 ml) and stirs for 5 hours at -10° C. to -3° C. togive benzylα-[3-benzyl-7-oxo-4-thia2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-.alpha.-(1-morpholinoethylidene)acetate,cools to -35° C. to -30° C., adds pyridine (0.27 ml) and bromine incarbon tetrachloride (1 mmole/ml: 3.2 ml), and stirs for 20 minutes togive benzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo]3,2,0]hept-2-en-6-yl]hept-2-en-6-yl]hept-2-en-6-yl]α-(1-morpholino-2-bromoethylidene)acetate,adds 5% hydrochloric acid (13 ml) and methanol (50 ml), and kept at 0°C. overnight to hydrolyze and cyclize giving the cephem product. Thesolvent is removed under reduced pressure, and the residual solution isextracted with ethyl acetate. The extract solution is washed withsaturated saline and water, dried over sodium sulfate, and purified bychromatography over silica gel containing 10% water. The fractionscontaining the product are combined and evaporated. Recrystallization ofthe residue from a mixture of methanol, ether, and hexane gives benzyl7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate, m.p. 149°-162° C.

NMR: δ^(CDCl).sbsp.3 3.28d2H, 3.63s2H, 4.98d(5Hz) 1H, 5.30s2H, 5.60dd(5;8Hz)1H, 6.37d(8Hz)1H, 7.4s+7.4s10H, 11.6brs1H. IR: ν_(max) ^(CHCl) ₃3420, 1785, 1680, 1615 cm⁻¹.

Example 21.--III

(i) To a solution of benzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-isopropenylacetate(4.22 g) in dichloromethane and methanol (5:1 ) is introduced ozonizedoxygen until the blue color of the solution does not fade out. Then thesolution is mixed with dimethyl sulfide, washed with water, dried, andconcentrated. The obtained residue is purified by chromatography oversilica gel containing 10 % water to give benzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate(2.98 g: 70.28%).

(ii) One adds triethylamine (1.42 ml), and methanesulfonyl chloride(0.41 ml) to a solution of benzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate(2.12 g) in tetrahydrofuran (30 ml) at -30° C., stirs for 70 minutes togive benzylα-[3-phenoxymethyl-7-oxo4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(methanesulfonyloxyethylidene)acetate,adds morphline (0.6 ml) and stirs for 4 hours 50 minutes at 0° C. togive benzylα-[3-phenoxymethyl-7-oxo-4-thia2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate,cools to -50° C., adds pyridine (0.385 ml) and bromine (0.25 ml), andstirs for 30 minutes to give benzylα-[3-phenoxymethyl-7-oxo-4-thia-2,6-bicyclo[3,2,0]hept-2-en-6-yl]-.alpha.(1-morpholino-2-bromoethylidene)acetate,adds 5% hydrochloric acid (36 ml), methanol (42.5 ml), andtetrahydrofuran (12.5 ml) to give clear solution. The solution isconcentrated, the resulting solution being extracted with ethyl acetate,washed with saturated saline, dried over sodium sulfate, andconcentrated to give residue (2.31 g). Purification of the residue bychromatography over silica gel containing 10% water gives benzyl7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate (1.11 g). m.p.126°-127° C.

PART IV Ozonolysis Example 1.--IV

To a solution of methylα-[4-acetylthio-3-phthalimido2-oxoazetidin-1-yl]-α-isopropenyl acetate(200 mg) in methylene chloride (10 ml) is introduced excess ozone at -5°C. After the gas at the outlet makes a potassium iodide starch papercoloured, the reaction mixture is concentrated to 2 ml, mixed with asolution of sodium borohydride (50 mg) in methanol (10 ml), and stirredfor 30 minutes. The reaction mixture is concentrated and dissolved inmethylene chloride, washed with water, dried, and evaporated. Theresidue is recrystallized from a mixture of methylene chloride and etherto give methyl α-[4-acetylthio3-phthalimido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate (157 mg). Yield: 78%. m.p. 178°-183° C.

Example 2. --IV

To a solution of α-[4-acetylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-isopropenyl acetic acid(100 mg) in methanol (10 ml) at 0° C. is introduced excess ozone. Afterthe gas at the outlet makes a potassium iodide starch paper coloured,the reaction mixture is bubbled with sulfur dioxide gas. The reactionmixture is concentrated, and the obtained residue is dissolved inaqueous solution of sodium hydrogen carbonate, washed with ether,neutralized with hydrochloric acid, and extracted with methylenechloride. The extract solution is washed with water, dried, andevaporated to giveα-[4-acetylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-acetylacetic acid(64 mg). Yield: 63%. Foam. IR: ν_(max) ^(CHCl).sbsp.3 1780, 1730, 1680cm⁻¹.

Example 3.--IV

To a stirred solution of 2,2,2-trichloroethylα-[4-(2-benzothiazolyl)dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-isopropenyl-acetate(1.76 g) in a mixture of methylene chloride (70 ml) and methanol (18ml), is introduced ozone under cooling with dry ice acetone until thesolution appears faint blue in color. After introducing nitrogen gas,the reaction mixture is treated with sulfur dioxide gas until thesolution appears faint yellow in color (about 30 seconds), and isconcentrated. The resulted residue is extracted with methylene chloride,washed with saline, dried, and concentrated to give powdery residue(1.35 g). Purification of the residue by chromatograhy over silica gel(30 g) gives 2,2,2-trichloroethylα-[4-(2-benzothiazolyl)dithio-3-phenoxyacetamido-2-oxazetidin-1-yl]-α-(1-hydroxyethylidiene)-acetate(1.09 g; Yield: 62.0%; m.p. 130°-131° C.), and 2,2,2-trichloroethylα-[4-(2-benzothiazolyl)dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1,1-dimethoxyethyl)-acetate(0.30 g; Yield: 15.6%9.

                                      TABLE V                                     __________________________________________________________________________     ##STR117##                                                                   Re-                                                                           act-                                      Temper-                                                                            Reducing                                                                            (12)                     ion                                                                              (11)                          Solvent  ature                                                                              reagent                                                                             Crop Yield               No.                                                                              R.sup.1 R.sup.2  R.sup.3  (mg)                                                                              (ml)     (°C.)                                                                       (ml)  (mg) (%)                 __________________________________________________________________________        ##STR118##                                                                           COCH.sub.3                                                                             CH.sub.3 15100                                                                             CH.sub.2 Cl.sub.2 300                                                                  -30  CH.sub.3 SCH.sub.3                                                                  10900                                                                              71.5                2                                                                                 ##STR119##                                                                           COCH.sub.3                                                                             CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      5100                                                                              CH.sub.2 Cl.sub.2 +CH.sub.3 OH 200+50                                                  -70  CH.sub.3 SCH.sub.3                                                                  4850 95.0                3                                                                                 ##STR120##                                                                           COCH.sub.3                                                                             CHPh.sub.2                                                                             4200                                                                              CH.sub.2 Cl.sub.2 +CH.sub.3 OH 50+50                                                   d.a. CH.sub.3 SCH.sub.3                                                                  3100 74.0                4                                                                                 ##STR121##                                                                           COCH.sub.3                                                                             CH.sub.2 CCl.sub.3                                                                     8000                                                                              CH.sub.2 Cl.sub.2 +CH.sub.3 OH 240+80                                                  d.a. CH.sub.3 SCH.sub.3                                                                  7800 97.0                5                                                                                 ##STR122##                                                                            ##STR123##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      106 CH.sub.2 Cl.sub.2 +CH.sub.3 OH 5+1                                                     -30  CH.sub.3 SCH.sub.3                                                                  103  97                  6                                                                                 ##STR124##                                                                            ##STR125##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      272 CH.sub.2 Cl.sub.2 +CH.sub.3 OH 10+3                                                    -78  CH.sub.3 SCH.sub.3                                                                  218  80                  7                                                                                 ##STR126##                                                                            ##STR127##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      950 CH.sub.2 Cl.sub.2 50                                                                   d.a. CH.sub.3 SCH.sub.3                                                                  540  56.7                8                                                                                 ##STR128##                                                                            ##STR129##                                                                            CHPh.sub.2                                                                             1000                                                                              CH.sub.2 Cl.sub.2 +CH.sub.3 OH 50+20                                                   d.a. CH.sub.3 SCH.sub.3                                                                  960  96                  9                                                                                 ##STR130##                                                                            ##STR131##                                                                            CH.sub.2 CCl.sub. 3                                                                    2500                                                                              CH.sub.2 Cl.sub.2 +CH.sub.3 OH 250+50                                                  -65  CH.sub.3 SCH.sub.3                                                                  1670 66                  10                                                                                ##STR132##                                                                            ##STR133##                                                                            CH.sub.2 CCl.sub.3                                                                     8200                                                                              CH.sub.2 Cl.sub.2 500                                                                  d.a. CH.sub.3 SCH.sub.3                                                                  7100 86.3                11                                                                                ##STR134##                                                                            ##STR135##                                                                            CH.sub.2 CCl.sub.3                                                                     1300                                                                              CH.sub.2 Cl.sub.2 +MeOH 65+13                                                          d.a. NaHSO.sub.3 0.21g                                                                   (II)805 61.7                                                                  α-(1,1-dimethox                                                         y- ethyl)derivative                                                           250 17.9                 12                                                                                ##STR136##                                                                            ##STR137##                                                                            CH.sub.2 CCl.sub.3                                                                     1300                                                                              CH.sub.2 Cl.sub.2 +MeOH  65+13                                                         d.a. SO.sub.2 0.21g                                                                      (II)770 59.1                                                                  α-(1,1-dimethox                                                         y- ethyl)derivative                                                           290                      __________________________________________________________________________                                                         20.8                 

                                      TABLE VI                                    __________________________________________________________________________     ##STR138##                                                                                                              NMR:.sub.δ.sup.CDCl.sbsp.                                               3 (60Mc)                                                                      (Numbers in parentheses            No.                                                                              R.sup.1 R.sup.2  R.sup.3  mp.  IR:ν .sub.max.sup.CHCl.sbsp.3(cm.sup.                                      -1)      show coupling constants :          __________________________________________________________________________                                               cps)                                   ##STR139##                                                                           COCH.sub.3                                                                             CH.sub.3 178°- 183° C.                                                        1786,1772,1725 1662,1618.                                                              2.27s3H,2.33s3H,3.86s3H,5.77d(5                                               )1H, 6.12d(5)1H,7.75m4H,12.3s1H                                               .                                  2                                                                                 ##STR140##                                                                           COCH.sub.3                                                                             CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      Foam 3428,1783,1700, 1608.                                                                  2.26s3H,2.30s3H,4.55s2H,5.2q1H,                                                5.32s2H,5.93d(5)1H, 6.9-8.4m10                                               H,12.17s1H.                        3                                                                                 ##STR141##                                                                           COCH.sub.3                                                                             CHPh.sub.2                                                                             Foam 3420,1770,1690, 1480.                                                                  2.18s3H,2.23s3H,4.55s2H,                                                      5.13-5.38q1H,5.93d(4.5)1H,                                                    6.80-7.47m7H,12.23s1H.             4                                                                                 ##STR142##                                                                           COCH.sub.3                                                                             CH.sub.2 CCl.sub.3                                                                     Powder                                                                             3430,1780,1690.                                                                        2.2756H,4.5352H,4.74+4.86ABq(12                                               )2H, 5.1-5.37mlH, 6.02d(5)1H,6.                                               77-7.30m5H,11.81s1H.               5                                                                                 ##STR143##                                                                            ##STR144##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      Oil  3440,1780,1713, 1667,1608.                                                             0.1-1.33m5H,2.24s3H,3.96D(7)2H,                                                4.50x2H,5.10mlH, 5.20s2H,5.74d                                               (5)1H,6.70-8.14m9H,12.10s1H.       6                                                                                 ##STR145##                                                                            ##STR146##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      56°-  58° C.                                                         3386,1777,1729, 1694,1670.                                                             1.40s9H,2.23s3H,3.02s2H,4.60s2H                                               , 5.35s2H,5.28-5.45m 2,H,6.75-8                                               .30mlOH,12.17s1H.                  7                                                                                 ##STR147##                                                                            ##STR148##                                                                            CH.sub.2 C.sub.6 H.sub.4 NO.sub.2                                                      Oil  3430,1778,1686, 1602.                                                                  2.35s3H,4.55s2H,4.87- 5.37m3H,                                                .42d(4.5)1H,6.75- 7.97m13H,12.1                                               4s1H.                              8                                                                                 ##STR149##                                                                            ##STR150##                                                                            CHpH.sub.2                                                                             Powder                                                                             3430,1779,1690.                                                                        2.30s3H,4.58s2H,5.13dd(5;8)1H,                                                .43d(5)1H,6.9-8.0m 21H,12.25s1H                                               .                                  9                                                                                 ##STR151##                                                                            ##STR152##                                                                            CH.sub.2 CCl.sub.3                                                                     130°- 132° C.                                                        3440,1781,1690.                                                                        2.40s3H,4.62s2H4.68ABq2H,                                                     5.13dd(5;8)1H,5.63d(5)                                                        1H,6.8-8.0m1OH,11.8s1H.            10                                                                                ##STR153##                                                                            ##STR154##                                                                            CH.sub.2 CCl.sub.3                                                                     Powder                                                                             3430,1772,1668, 1602.                                                                  2.40s3H,3.72s2H,4.47+4.73ABq(12                                               )2H, 4.87dd(5;8)1H, 5.52d(5)1H,                                               6.40d(8)1H,7.17-7.93m9H,11.73s1                                               H.                                 11                                                                                ##STR155##                                                                            ##STR156##                                                                            CH.sub.2 CCl.sub.3                                                                     116°- 119°  C.                                                       3425,1784,1762, 1693.                                                                  1.63s3H,3.29s6H,4.45s2H,4.58+                                                 4.79ABq(14)2H,4.79s1H,                                                        5.47-5.71m2H,6.60-7.87m1OH.        α-(1,1-dimethoxyethyl)derivative                                        __________________________________________________________________________

Example 4.--

To a solution of α-[4-substituted (R²) thio-3-substituted amino(R¹)-2-oxoazetidin-1-yl]-α-isopropenyl-acetate ester (R³) in a solventis introduced ozone under cooling. After the gas at the outlet makespotassium iodide starch paper blue, introduction of ozone is ceased, andexcess ozone is removed by introduction of nitrogen gas. Reducingreagent is added to the reaction mixture and let react for 10 to 30minutes. After the reduction, the solvent is evaporated, and the residueis crystallized, or the reaction mixture is filtered through a layer ofsilica gel, and the filtrate is evaporated to give α-[4-substitutedthio-3-substitutedamino-2-oxoazetidin-1-yl]α-(1-hydroxyethylidene)acetic acid ester.

The reaction conditions are shonw in Table V, and the physical constantsof the products are shown in Table VI.

Example 5.--IV

According to a procedure similar to that of Example 4, the following4-substituted thio-3-substituted amino-2-oxo-α-(1-hydroxyethylidene oracetyl)azetidine-1-acetic acid esters are prepared from thecorresponding α-isopropenyl-azetidine derivatives.

(1) p-methoxybenzylα-[4-(2-methyl-1,3,4-thiadiazol-5-yl)dithio-3-(2-theienylacetamido)-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)-acetate;

(2) 2,2,2-trichloroethylα-[4-(o:nitrophenyl)dithio-3-(2,2,2-trichloroethoxycarbonamide)-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate;

(3) diphenylmethylα-[4-cycopropylmethoxycarbonylthio-3-tert.-butoxycarbonamido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate;

(4) 2,2,2-trichloroethyl α-[4-acetylthio-3-(N-tertiarybutoxycarbonamido-α-phenylglycinamido)-2oxoazetidin-1-yl]-α-(1-hydroxyethylidene)-acetate;

(50 p--bromophenacyl α-[4-(benzothiazol-2-yl)dithio-3-(2,2-dimethyl-3-nitroso-4-phenyl-5-oxoimidazolidin-1-yl)2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene(acetate;

(6) p-nitroenzylα-[4-(1,3,4-thiadiazol-5-yl)dithio-3-(o-nitrobenzylideneamino)-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)-acetate;

(7) methylα-[4-benzylidithio-3-(2,6-dimethoxybenzoylamino)-2-oxoazetidin-1-yl]-α-(lphydroxyethylidene)acetate;

(8) ethylα-[4-acetylthio-3-cyanoacetamido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate;

(9) acetoxymethyl[4-acetylthio-3-(α-indanyloxcarbonyl-α-phenylacetamido)-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate;and

(10) disodiumα-[4-pyridithio-3-(α-sulfo-α-phenylacetamido)-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate.

What we claim is:
 1. A process for cyclizing a compound represented bythe formula ##STR157## wherein R' represents a member selected from thegroup consisting of (1) hydrogen, (2) C₁ to C₄ alkyl, (3) phenyl, (4)α-chlorobenzyl, (5) ArCQQ, (6) Ar-G-CQQ wherein Q represents hydrogen ormethyl, G represents oxygen or sulfur and Ar represents (a) phenyl, (b)dihydrophenyl, (c) monocyclic heterocyclic aromatic containing from 1 to4 hereto atoms selected from the group of nitrogen, oxygen and sulfur or(d) one of said groups (a) to (c) substituted by an inert group selectedfrom the group of alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbonatoms, chlorine, bromine, iodine, fluorine, trifluoromethyl hydroxy,cyano, aminomethyl, amino and nitro, or ##STR158## representsphthalimido, COX represents carboxy or protected carboxy, andHalrepresents a halogen atom, which comprises the step of treating the saidcompound with a member of the group consisting of acid, base, solventand a solvent together with a catalyzer selected from the group of aneutral or basic silica gel, alumina, diatomaceous earth and fluorisilto give a compound represented by the formula ##STR159##
 2. A processaccording to claim 1 wherein the acid is a mineral acid, sulfonic acid,phosphonic acid, or carboxylic acid, or their salts with a weak base, ortheir acidic salts.
 3. A process according to claim 1 wherein the baseis a weak base.
 4. A process according to claim 1 wherein the solvent isan amide, alcohol, or water solvents as the cyclization reagent.
 5. Aprocess for preparing a compound of the following formula: ##STR160##wherein R' and COX are as defined in claim 1 which comprises the step oftreating a compound of the following formula: ##STR161## wherein R' andCOX are as defined above, Hal is halogen, and Y is morpholino-4-yl, C₄₋₈alkyleneamino, C₂₋₆ dialkylamino or C₁₄₋₂₀ diaralkylamino, to the actionof an aqueous protonic acid in a solvent selected from alcoholic,etheric and halohydrocarbon solvent.